Novel proteins and nucleic acids encoding same

ABSTRACT

Disclosed herein are nucleic acid sequences that encode novel polypeptides. Also disclosed are polypeptides encoded by these nucleic acid sequences, and antibodies, which immunospecifically-bind to the polypeptide, as well as derivatives, variants, mutants, or fragments of the aforementioned polypeptide, polynucleotide, or antibody. The invention further discloses therapeutic, diagnostic and research methods for diagnosis, treatment, and prevention of disorders involving any one of these novel human nucleic acids and proteins.

RELATED APPLICATIONS

[0001] This application claims priority from U.S. Ser. No. 10/174,372,filed Jun. 17, 2002; U.S. Ser. No. 09/898,994 filed Jul. 3, 2001; U.S. SNo. 60/215,854, filed Jul. 3, 2000; U.S. S No. 60/215,856, filed Jul. 3,2000; U.S. S No. 60/215,902, filed Jul. 3, 2000; U.S. S No. 60/216,585,filed Jul. 7, 2000; U.S. S No. 60/216,586, filed on Jul. 7, 2001; U.S. SNo. 60/216,722, filed Jul. 7, 2000; U.S. S No. 60/218,622, filed Jul.17, 2000; U.S. S No. 60/218,992, filed on Jul. 17, 2000; U.S. S No.60/221,285, filed Jul. 27, 2000; U.S. S No. 60/268,734, filed Feb. 14,2001; U.S. S No. 60/274,260, filed Mar. 8, 2001; and U.S. S No.60/279,856, filed Mar. 29, 2001; each of which is incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

[0002] The invention generally relates to nucleic acids andpolypeptides. More particularly, the invention relates to nucleic acidsencoding novel molecule (MOL) polypeptides, as well as vectors, hostcells, antibodies, and recombinant methods for producing these nucleicacids and polypeptides.

SUMMARY OF THE INVENTION

[0003] The invention is based in part upon the discovery of nucleic acidsequences encoding novel polypeptides. The novel nucleic acids andpolypeptides are referred to herein as MOLX, or MOL1, MOL2, MOL3, MOL4,MOL5, MOL6, MOL7, and MOL8 nucleic acids and polypeptides. These nucleicacids and polypeptides, as well as derivatives, homologs, analogs andfragments thereof, will hereinafter be collectively designated as “MOLX”nucleic acid or polypeptide sequences.

[0004] In one aspect, the invention provides an isolated MOLX nucleicacid molecule encoding a MOLX polypeptide that includes a nucleic acidsequence that has identity to the nucleic acids disclosed in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23. In some embodiments, theMOLX nucleic acid molecule will hybridize under stringent conditions toa nucleic acid sequence complementary to a nucleic acid molecule thatincludes a protein-coding sequence of a MOLX nucleic acid sequence. Theinvention also includes an isolated nucleic acid that encodes a MOLXpolypeptide, or a fragment, homolog, analog or derivative thereof. Forexample, the nucleic acid can encode a polypeptide at least 80%identical to a polypeptide comprising the amino acid sequences of SEQ IDNOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. The nucleic acid canbe, for example, a genomic DNA fragment or a cDNA molecule that includesthe nucleic acid sequence of any of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13,15, 17, 19, 21, and 23.

[0005] Also included in the invention is an oligonucleotide, e.g., anoligonucleotide which includes at least 6 contiguous nucleotides of aMOLX nucleic acid (e.g., SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19,21, and 23) or a complement of said oligonucleotide.

[0006] Also included in the invention are substantially purified MOLXpolypeptides (SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and24). In certain embodiments, the MOLX polypeptides include an amino acidsequence that is substantially identical to the amino acid sequence of ahuman MOLX polypeptide.

[0007] The invention also features antibodies that immunoselectivelybind to MOLX polypeptides, or fragments, homologs, analogs orderivatives thereof.

[0008] In another aspect, the invention includes pharmaceuticalcompositions that include therapeutically- or prophylactically-effectiveamounts of a therapeutic and a pharmaceutically-acceptable carrier. Thetherapeutic can be, e.g., a MOLX nucleic acid, a MOLX polypeptide, or anantibody specific for a MOLX polypeptide. In a further aspect, theinvention includes, in one or more containers, a therapeutically- orprophylactically-effective amount of this pharmaceutical composition.

[0009] In a further aspect, the invention includes a method of producinga polypeptide by culturing a cell that includes a MOLX nucleic acid,under conditions allowing for expression of the MOLX polypeptide encodedby the DNA. If desired, the MOLX polypeptide can then be recovered.

[0010] In another aspect, the invention includes a method of detectingthe presence of a MOLX polypeptide in a sample. In the method, a sampleis contacted with a compound that selectively binds to the polypeptideunder conditions allowing for formation of a complex between thepolypeptide and the compound. The complex is detected, if present,thereby identifying the MOLX polypeptide within the sample.

[0011] The invention also includes methods to identify specific cell ortissue types based on their expression of a MOLX.

[0012] Also included in the invention is a method of detecting thepresence of a MOLX nucleic acid molecule in a sample by contacting thesample with a MOLX nucleic acid probe or primer, and detecting whetherthe nucleic acid probe or primer bound to a MOLX nucleic acid moleculein the sample.

[0013] In a further aspect, the invention provides a method formodulating the activity of a MOLX polypeptide by contacting a cellsample that includes the MOLX polypeptide with a compound that binds tothe MOLX polypeptide in an amount sufficient to modulate the activity ofsaid polypeptide. The compound can be, e.g., a small molecule, such as anucleic acid, peptide, polypeptide, peptidomimetic, carbohydrate, lipidor other organic (carbon-containing) or inorganic molecule, as furtherdescribed herein.

[0014] Also within the scope of the invention is the use of atherapeutic in the manufacture of a medicament for treating orpreventing disorders or syndromes including, e.g., endometriosis,fertility disorders, hypercoagulation, idiopathic thrombocytopenicpurpura, immunodeficiencies, systemic lupus erythematosus, asthma,emphysema, scleroderma, allergy, ARDS, Von Hippel-Lindau (VHL) syndrome,Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia,Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy,multiple sclerosis, ulcers, ataxia-telangiectasia, leukodystrophies,behavioral disorders, addiction, anxiety, pain, neuroprotection,osteoporosis, arthritis, ankylosing spondylitis, scoliosis, diabetes,autoimmune disease, myasthenia gravis, muscular dystrophy, renal arterystenosis, interstitial nephritis, glomerulonephritis, polycystic kidneydisease, systemic lupus erythematosus, renal tubular acidosis, IgAnephropathy, Lesch-Nyhan syndrome, developmental disorders, growthdisorders, and/or wounds, cardiomyopathy, atherosclerosis, hypertension,congenital heart defects, aortic stenosis, atrial septal defect (ASD),atrioventricular (A-V) canal defect, ductus arteriosus, pulmonarystenosis, subaortic stenosis, ventricular septal defect (VSD), valvediseases, obesity, transplantation, hemophilia, hypercoagulation,idiopathic thrombocytopenic purpura, immunodeficiencies, graft versushost disease (GVHD), lymphaedema, adrenoleukodystrophy, congenitaladrenal hyperplasia, neuronal developmental, organizational, mediatedand interactive disorders and disease; endocrine dysfunctions, growthand reproductive disorders, injury repair, cancer including but notlimited to lung or breast cancer, endocrine disorders, inflammatorydisorders, gastro-intestinal disorders and disorders of the respiratorysystem, Rheumatoid arthritis (RA), CNS disorders, Down syndrome,Schizophrenia, nutritional deficiencies, primary open-angle glaucoma(POAG), and bone disorders, hematopoietic disorders, or other disorders.The therapeutic can be, e.g., a MOLX nucleic acid, a MOLX polypeptide,or a MOLX-specific antibody, or biologically-active derivatives orfragments thereof.

[0015] For example, the compositions of the present invention will haveefficacy for treatment of patients suffering from: Cancer includingendometriosis, fertility disorders, hypercoagulation, idiopathicthrombocytopenic purpura, immunodeficiencies, systemic lupuserythematosus, asthma, emphysema, scleroderma, allergy, ARDS, VonHippel-Lindau (VHL) syndrome, Alzheimer's disease, stroke, tuberoussclerosis, hypercalceimia, Parkinson's disease, Huntington's disease,cerebral palsy, epilepsy, multiple sclerosis, ulcers,ataxia-telangiectasia, leukodystrophies, behavioral disorders,addiction, anxiety, pain, neuroprotection, osteoporosis, arthritis,ankylosing spondylitis, scoliosis, diabetes, autoimmune disease,myasthenia gravis, muscular dystrophy, renal artery stenosis,interstitial nephritis, glomerulonephritis, polycystic kidney disease,systemic lupus erythematosus, renal tubular acidosis, IgA nephropathy,Lesch-Nyhan syndrome, developmental disorders, growth disorders, and/orwounds, cardiomyopathy, atherosclerosis, hypertension, congenital heartdefects, aortic stenosis, atrial septal defect (ASD), atrioventricular(A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaorticstenosis, ventricular septal defect (VSD), valve diseases, obesity,transplantation, hemophilia, hypercoagulation, idiopathicthrombocytopenic purpura, immunodeficiencies, graft versus host disease(GVHD), lymphaedema, adrenoleukodystrophy, congenital adrenalhyperplasia, neuronal developmental, organizational, mediated andinteractive disorders and disease; endocrine dysfunctions, growth andreproductive disorders, injury repair, cancer including but not limitedto lung or breast cancer, endocrine disorders, inflammatory disorders,gastro-intestinal disorders and disorders of the respiratory system,Rheumatoid arthritis (RA), CNS disorders, Down syndrome, Schizophrenia,nutritional deficiencies, primary open-angle glaucoma (POAG), and bonedisorders, hematopoietic disorders and/or other pathologies anddisorders of the like.

[0016] The polypeptides can be used as immunogens to produce antibodiesspecific for the invention and as vaccines. They can also be used toscreen for potential agonist and antagonist compounds. For example, acDNA encoding MOLX may be useful in gene therapy, and MOLX may be usefulwhen administered to a subject in need thereof. By way of nonlimitingexample, the compositions of the present invention will have efficacyfor treatment of patients suffering from endometriosis, fertilitydisorders, hypercoagulation, idiopathic thrombocytopenic purpura,immunodeficiencies, systemic lupus erythematosus, asthma, emphysema,scieroderma, allergy, ARDS, Von Hippel-Lindau (VHL) syndrome,Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia,Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy,multiple sclerosis, ulcers, ataxia-telangiectasia, leukodystrophies,behavioral disorders, addiction, anxiety, pain, neuroprotection,osteoporosis, arthritis, ankylosing spondylitis, scoliosis, diabetes,autoimmune disease, myasthenia gravis, muscular dystrophy, renal arterystenosis, interstitial nephritis, glomerulonephritis, polycystic kidneydisease, systemic lupus erythematosus, renal tubular acidosis, IgAnephropathy, Lesch-Nyhan syndrome, developmental disorders, growthdisorders, and/or wounds, cardiomyopathy, atherosclerosis, hypertension,congenital heart defects, aortic stenosis, atrial septal defect (ASD),atrioventricular (A-V) canal defect, ductus arteriosus, pulmonarystenosis, subaortic stenosis, ventricular septal defect (VSD), valvediseases, obesity, transplantation, hemophilia, hypercoagulation,idiopathic thrombocytopenic purpura, immunodeficiencies, graft versushost disease (GVHD), lymphaedema, adrenoleukodystrophy, congenitaladrenal hyperplasia, neuronal developmental, organizational, mediatedand interactive disorders and disease; endocrine dysfunctions, growthand reproductive disorders, injury repair, cancer including but notlimited to lung or breast cancer, endocrine disorders, inflammatorydisorders, gastro-intestinal disorders and disorders of the respiratorysystem, Rheumatoid arthritis (RA), CNS disorders, Down syndrome,Schizophrenia, nutritional deficiencies, primary open-angle glaucoma(POAG), and bone disorders, hematopoietic disorders and/or otherpathologies and disorders.

[0017] The invention further includes a method for screening for amodulator of disorders or syndromes including, e.g., endometriosis,fertility disorders, hypercoagulation, idiopathic thrombocytopenicpurpura, immunodeficiencies, systemic lupus erythematosus, asthma,emphysema, scieroderma, allergy, ARDS, Von Hippel-Lindau (VHL) syndrome,Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia,Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy,multiple sclerosis, ulcers, ataxia-telangiectasia, leukodystrophies,behavioral disorders, addiction, anxiety, pain, neuroprotection,osteoporosis, arthritis, ankylosing spondylitis, scoliosis, diabetes,autoimmune disease, myasthenia gravis, muscular dystrophy, renal arterystenosis, interstitial nephritis, glomerulonephritis, polycystic kidneydisease, systemic lupus erythematosus, renal tubular acidosis, IgAnephropathy, Lesch-Nyhan syndrome, developmental disorders, growthdisorders, and/or wounds, cardiomyopathy, atherosclerosis, hypertension,congenital heart defects, aortic stenosis, atrial septal defect (ASD),atrioventricular (A-V) canal defect, ductus arteriosus, pulmonarystenosis, subaortic stenosis, ventricular septal defect (VSD), valvediseases, obesity, transplantation, hemophilia, hypercoagulation,idiopathic thrombocytopenic purpura, immunodeficiencies, graft versushost disease (GVHD), lymphaedema, adrenoleukodystrophy, congenitaladrenal hyperplasia, neuronal developmental, organizational, mediatedand interactive disorders and disease; endocrine dysfunctions, growthand reproductive disorders, injury repair, cancer including but notlimited to lung or breast cancer, endocrine disorders, inflammatorydisorders, gastro-intestinal disorders and disorders of the respiratorysystem, Rheumatoid arthritis (RA), CNS disorders, Down syndrome,Schizophrenia, nutritional deficiencies, primary open-angle glaucoma(POAG), and bone disorders, hematopoietic disorders or other disordersrelated to cell signal processing and metabolic pathway modulation. Themethod includes contacting a test compound with a MOLX polypeptide anddetermining if the test compound binds to said MOLX polypeptide. Bindingof the test compound to the MOLX polypeptide indicates the test compoundis a modulator of activity, or of latency or predisposition to theaforementioned disorders or syndromes.

[0018] Also within the scope of the invention is a method for screeningfor a modulator of activity, or of latency or predisposition to andisorders or syndromes including, e.g., endometriosis, fertilitydisorders, hypercoagulation, idiopathic thrombocytopenic purpura,immunodeficiencies, systemic lupus erythematosus, asthma, emphysema,scleroderma, allergy, ARDS, Von Hippel-Lindau (VHL) syndrome,Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia,Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy,multiple sclerosis, ulcers, ataxia-telangiectasia, leukodystrophies,behavioral disorders, addiction, anxiety, pain, neuroprotection,osteoporosis, arthritis, ankylosing spondylitis, scoliosis, diabetes,autoimmune disease, myasthenia gravis, muscular dystrophy, renal arterystenosis, interstitial nephritis, glomerulonephritis, polycystic kidneydisease, systemic lupus erythematosus, renal tubular acidosis, IgAnephropathy, Lesch-Nyhan syndrome, developmental disorders, growthdisorders, and/or wounds, cardiomyopathy, atherosclerosis, hypertension,congenital heart defects, aortic stenosis, atrial septal defect (ASD),atrioventricular (A-V) canal defect, ductus arteriosus, pulmonarystenosis, subaortic stenosis, ventricular septal defect (VSD), valvediseases, obesity, transplantation, hemophilia, hypercoagulation,idiopathic thrombocytopenic purpura, immunodeficiencies, graft versushost disease (GVHD), lymphaedema, adrenoleukodystrophy, congenitaladrenal hyperplasia, neuronal developmental, organizational, mediatedand interactive disorders and disease; endocrine dysfunctions, growthand reproductive disorders, injury repair, cancer including but notlimited to lung or breast cancer, endocrine disorders, inflammatorydisorders, gastro-intestinal disorders and disorders of the respiratorysystem, Rheumatoid arthritis (RA), CNS disorders, Down syndrome,Schizophrenia, nutritional deficiencies, primary open-angle glaucoma(POAG), and bone disorders, hematopoietic disorders or other disordersrelated to cell signal processing and metabolic pathway modulation byadministering a test compound to a test animal at increased risk for theaforementioned disorders or syndromes. The test animal expresses arecombinant polypeptide encoded by a MOLX nucleic acid. Expression oractivity of MOLX polypeptide is then measured in the test animal, as isexpression or activity of the protein in a control animal whichrecombinantly-expresses MOLX polypeptide and is not at increased riskfor the disorder or syndrome. Next, the expression of MOLX polypeptidein both the test animal and the control animal is compared. A change inthe activity of MOLX polypeptide in the test animal relative to thecontrol animal indicates the test compound is a modulator of latency ofthe disorder or syndrome.

[0019] In yet another aspect, the invention includes a method fordetermining the presence of or predisposition to a disease associatedwith altered levels of a MOLX polypeptide, a MOLX nucleic acid, or both,in a subject (e.g., a human subject). The method includes measuring theamount of the MOLX polypeptide in a test sample from the subject andcomparing the amount of the polypeptide in the test sample to the amountof the MOLX polypeptide present in a control sample. An alteration inthe level of the MOLX polypeptide in the test sample as compared to thecontrol sample indicates the presence of or predisposition to a diseasein the subject. Preferably, the predisposition includes, e.g.,endometriosis, fertility disorders, hypercoagulation, idiopathicthrombocytopenic purpura, immunodeficiencies, systemic lupuserythematosus, asthma, emphysema, scleroderma, allergy, ARDS, VonHippel-Lindau (VHL) syndrome, Alzheimer's disease, stroke, tuberoussclerosis, hypercalceimia, Parkinson's disease, Huntington's disease,cerebral palsy, epilepsy, multiple sclerosis, ulcers,ataxia-telangiectasia, leukodystrophies, behavioral disorders,addiction, anxiety, pain, neuroprotection, osteoporosis, arthritis,ankylosing spondylitis, scoliosis, diabetes, autoimmune disease,myasthenia gravis, muscular dystrophy, renal artery stenosis,interstitial nephritis, glomerulonephritis, polycystic kidney disease,systemic lupus erythematosus, renal tubular acidosis, IgA nephropathy,Lesch-Nyhan syndrome, developmental disorders, growth disorders, and/orwounds, cardiomyopathy, atherosclerosis, hypertension, congenital heartdefects, aortic stenosis, atrial septal defect (ASD), atrioventricular(A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaorticstenosis, ventricular septal defect (VSD), valve diseases, obesity,transplantation, hemophilia, hypercoagulation, idiopathicthrombocytopenic purpura, immunodeficiencies, graft versus host disease(GVHD), lymphaedema, adrenoleukodystrophy, congenital adrenalhyperplasia, neuronal developmental, organizational, mediated andinteractive disorders and disease; endocrine dysfunctions, growth andreproductive disorders, injury repair, cancer including but not limitedto lung or breast cancer, endocrine disorders, inflammatory disorders,gastro-intestinal disorders and disorders of the respiratory system,Rheumatoid arthritis (RA), CNS disorders, Down syndrome, Schizophrenia,nutritional deficiencies, primary open-angle glaucoma (POAG), and bonedisorders, hematopoietic disorders. Also, the expression levels of thenew polypeptides of the invention can be used in a method to screen forvarious cancers as well as to determine the stage of cancers.

[0020] In a further aspect, the invention includes a method of treatingor preventing a pathological condition associated with a disorder in amammal by administering to the subject a MOLX polypeptide, a MOLXnucleic acid, or a MOLX-specific antibody to a subject (e.g., a humansubject), in an amount sufficient to alleviate or prevent thepathological condition. In preferred embodiments, the disorder,includes, e.g., endometriosis, fertility disorders, hypercoagulation,idiopathic thrombocytopenic purpura, immunodeficiencies, systemic lupuserythematosus, asthma, emphysema, scleroderma, allergy, ARDS, VonHippel-Lindau (VHL) syndrome, Alzheimer's disease, stroke, tuberoussclerosis, hypercalceimia, Parkinson's disease, Huntington's disease,cerebral palsy, epilepsy, multiple sclerosis, ulcers,ataxia-telangiectasia, leukodystrophies, behavioral disorders,addiction, anxiety, pain, neuroprotection, osteoporosis, arthritis,ankylosing spondylitis, scoliosis, diabetes, autoimmune disease,myasthenia gravis, muscular dystrophy, renal artery stenosis,interstitial nephritis, glomerulonephritis, polycystic kidney disease,systemic lupus erythematosus, renal tubular acidosis, IgA nephropathy,Lesch-Nyhan syndrome, developmental disorders, growth disorders, and/orwounds, cardiomyopathy, atherosclerosis, hypertension, congenital heartdefects, aortic stenosis, atrial septal defect (ASD), atrioventricular(A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaorticstenosis, ventricular septal defect (VSD), valve diseases, obesity,transplantation, hemophilia, hypercoagulation, idiopathicthrombocytopenic purpura, immunodeficiencies, graft versus host disease(GVHD), lymphaedema, adrenoleukodystrophy, congenital adrenalhyperplasia, neuronal developmental, organizational, mediated andinteractive disorders and disease; endocrine dysfunctions, growth andreproductive disorders, injury repair, cancer including but not limitedto lung or breast cancer, endocrine disorders, inflammatory disorders,gastro-intestinal disorders and disorders of the respiratory system,Rheumatoid arthritis (RA), CNS disorders, Down syndrome, Schizophrenia,nutritional deficiencies, primary open-angle glaucoma (POAG), and bonedisorders, hematopoietic disorders, and/or other diseases or disorders.

[0021] In yet another aspect, the invention can be used in a method toidentity the cellular receptors and downstream effectors of theinvention by any one of a number of techniques commonly employed in theart. These include but are not limited to the two-hybrid system,affinity purification, co-precipitation with antibodies or otherspecific-interacting molecules.

[0022] Unless otherwise defined, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention belongs. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In the case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

[0023] Other features and advantages of the invention will be apparentfrom the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

[0024] The invention is based, in part, upon the discovery of novelnucleic acid sequences that encode novel polypeptides. The novel nucleicacids and their encoded polypeptides are referred to individually asMOL1, MOL2, MOL3, MOL4, MOL5, MOL6, MOL7, and MOL8. The nucleic acids,and their encoded polypeptides, are collectively designated herein as“MOLX”.

[0025] The novel MOLX nucleic acids of the invention include the nucleicacids whose sequences are provided in Tables 1A, 1D, 2A, 3A, 3D, 4A, 5A,5C, 5E, 6A, 7A, and 8A, inclusive (“Tables 1A-8A”), or a fragment,derivative, analog or homolog thereof. The novel MOLX proteins of theinvention include the protein fragments whose sequences are provided inTables 1B, 1E, 2B, 3B, 3E, 4B, 5B, 5D, SF, 6B, 7B, and 8B inclusive(“Tables 1B-8B”). The individual MOLX nucleic acids and proteins aredescribed below. Within the scope of this invention is a method of usingthese nucleic acids and peptides in the treatment or prevention of adisorder related to cell signaling or metabolic pathway modulation.

[0026] MOL1

[0027] MOL1a

[0028] A disclosed Notch-like nucleic acid of 7410 nucleotides, MOL1a,alternatively referred to as SC29674552_EXT, is shown in Table 1A. Thedisclosed MOL1a open reading frame (“ORF”) begins at the ATG initiationcodon at nucleotides 1-3 and terminates at a TGA codon at nucleotides7408-7410. In Table 1A, the start and stop codons are depicted with boldletters. TABLE 1A MOL1a nucleotide sequence. (SEQ ID NO:1)ATGCCCGCCCTGCGCCCCGCTCTGCTGTGGGCGCTGCTGGCGCTCTGGCTGTGCTGCGCGACCCCCGCGCATGCATTGCAGTGTCGAGATGGCTATGAACCCTGTGTAAATGAAGGAATGTGTGTTACCTACCACAATGGCACAGGATACTGCAAATGTCCAGAAGGCTTCTTGGGGGAATATTGTCAACATCGAGACCCCTGTGAGAAGAACCGCTGCCAGAATGGTGGGACTTGTGTGGCCCAGGCCATGCTGGGGAAAGCCACGTGCCGATGTGCCTCAGGGTTTACAGGAGAGGACTGCCAGTACTCGACATCTCATCCATGCTTTGTGTCTCGACCTTGCCTGAATGGCGGCACATGCCATATGCTCAGCCGGGATACCTATGAGTGCACCTGTCAAGTCGGGTTTACAGGTAAGGAGTGCCAATGGACGGATGCCTGCCTGTCTCATCCCTGTGCAAATGGAAGTACCTGTACCACTGTGGCCAACCAGTTCTCCTGCAAATGCCTCACAGGCTTCACAGGGCAGAAATGTGAGACTGATGTCAATGAGTGTGACATTCCAGGACACTGCCAGCATGGTGGCACCTGCCTCAACCTGCCTGGTTCCTACCAGTGCCAGTGCCCTCAGGGCTTCACACAGGCCAGTACTGTGACAGCCTGTATGTGCCCTGCACCCTCACCTTGTGTCAATGGAGGCACCTGTCGCCAGACTGGTGACTTCACTTTTGAGTGCCATTTACCAGGTTTTGAAGGGAGCACCTGTGAGAGGAATATTGATGACTGCCCTAACCACAGGTGTCAGAATGGAGGGGTTTGTGTGGATGGGGTCAACACTTACAACTGCCGCTGTCCCCCACAATGGACAGGACAGTTCTGCACAGAGGATGTGGATGAATGCCTGCTGCAGCCCAATGCCTGTCAAAACTGGGCACCTGTGCCAACCGCAATGGAGGCTATGGCTGTGTATGTGTCCAACGGCTGGAGTGGAGATGACTGCAGTGAGAACATTGATGATTGTGCTTTCGGCGCCTGTACTCCAGGCTCCACCTGCATCGACCGTGTGGCCTCCTTCTCTTGCATGTGCCCAGAGGGGAAGGCAGGTCTCCTGTGTCATCTGGATGATGCATGCATCAGCAATCCTTGCCACAAGGGGGCACTGTGTGACACGAACCCCCTAAATGGGCAATATATTTGCACCTGCCCACAAGGCTACAAAGGGGCTGACTGCACAGAAGATGTGGATGAATGTGCCATGGCCAATAGCAATCCTTGTGAGCATGCAGGAAAATGTGTGAACACGGATGGCGCCTTCCACTGTGAGTGTCTGAAGGGTTATGCAGGACCTCGTTGTGAGATGGACATCAATGAGTGCCATTCAGACCCCTGCCAGAATGATGCTACCTGTCTGGATAAGATTGGAGGCTTCACATGTCTGTGCATGCCAGGTTTCAAAGGTGTGCATTGTGAATTAGAAATAAATGAATGTCAGAGCAACCCTTGTGTGAACAATGGGCAGTGTGTGGATAAAGTCAATCGTTTCCAGTGCCTGTGTCCTCCTGGTTTCACTCGCCCAGTTTGCCAGATTGATATTGATGACTGTTCCAGTACTCCGTGTCTGAATGGGGCAAAGTGTATCGATCACCCGAATGGCTATGAATCCCAGTGTGCCACAGGTTTCACTGGTGTGTTGTGTGAGGAGACATTGACAACTGTGACCCCGATCCTTGCCACCATGGTCAGTGTCAGGATGGGTATTGATTCCTACACCTGCATCTGCAATCCCGGGTACATGGGCGCCATCTGCAGTGACCAGATTGATGAATGTTACAGCAGCCCTTGCCTGAACGATGGTCGCTGCATTGACCTGGTCAATGGCTACCAGTGCAACTGCCAGCCAGGCACGTCAGGTGTTAATTGTGAAATTAATTTTGATGACTGTGCAAGTAACCCTTGTATCCATGGAATCTGTATGGATGGCATTAATCGCTACAGTTGTGTCTGCTCACCAGGATTCACAGGGCAGAGATGTAACATTGACATTGATGAGTGTGCCTCCAATCCCTGTCGCAAGGGTGCAACATGTATCAACGGTGTGAATGGTTTCCGCTGTATATGCCCCGAGGGACCCCATCACCCCAGCTGCTACTCACAGGTGAACGAATGCCTGAGCAATCCCTGCATCCATGGAAACTGTACTGGAGGTCTCAGTGGATATAAGTGTCTCTGTGATGCAGGCTGGGTTGGCATCAACTGTGAAGTGGACAAAAATGAATGCCTTTCGAATCCATGCCAGAATGGAGGAACTTGTGACAATCTGGTGAATGGATACAGGTGTACTTGCAAGAAGGGCTTTAAAGGCTATAACTGCCAGGTGAATATTGATGAATGTGCCTCAAATCCATGCCTGAACCAAGGAACCTGCTTTGATGACATAAGTGGCTACACTTGCCACTGTGTGCTGCCATACACAGGTAAGAATTGTCAGACAGTATTGGCTCCCTGTTCCCCAAACCCTTGTGAGAATGCTGCTGTTTGCAAAGAGTCACCAAATTTTGAGAGTTATACTTGCTTGTGTGCTCCTGGCTGGCAAGGTCAGCGGTGTACCATTGACATTGACGAGTGTATCTCCAAGCCCTGCATGAACCATGGTCTCTGCCATAACACCCAGGGCAGCTACATGTGTGAATGTCCAGGATTTGATGGAGTCCATTGTGAGAACAACATCAATGAGTGCACTGAGAGCTCCTGTTTCAATGGTGGCACATGTTGTATGGATGGAGTGAATACTTTCTCCTGCCTCTGCCTTCCGGGTTTCACTGGGGATAAGTGCCAGACAGACATGAATGAGTGTCTGAGTGAACCCTGTAAGAATGGAGGGACCTGCTCTGACTACGTCAACAGTTACACTTGCAAGTGCCAGGCAGGATTTGATGGAGTCCATTGTGAGAACAACATCAATGAGTGCACTGAGAGCTCCTGTTTCAATGGTGGCACATGTGTTGATGGGATTAACTCCTTCTCTTGCTTGTGCCCTGTGGGTTTCACTGGATCCTTCTGCCTCCATGAGATCAATGAATGCAGCTCTCATCCATGCCTGAATGATGGAACGTGTGTTGATGGCCTGGGTACCTACCGCTGCAGCTGCCCCCTGGGCTACACTGGGAAAAACTGTCAGACCCTGGTGAATCTCTGCAGTCGGTCTCCATGTAAAAACAAAGGTACTTGCGTTCAGAAAAAAGCAGAGTCCCAGTGCCTATGTCCATCTGGATGGGCTGGTGCCTATTGTGACGTGCCCAATGTCTCTTGTGACATAGCAGCCTCCAGGAGAGGTGTGCTTGTTGAACACTTGTGCCAGCACTCAGGTGTCTGCATCAATGCTGGCAACACGCATTACTGTCAGTGCCCCCTGGGCTATACTGGGAGCTACTGTGAGGAGCAACTCGATGAGTGTGCGTCCAACCCCTGCCAGCACGGGGCAACATGCAGTGACTTCATTGGTGGATACAGATGCGAGTGTGTCCCAGGCTATCAGGGTGTCAACTGTGAGTATGAAGTGGATGAGTGCCAGAATCAGCCCTGCCAGAATGGAGGCACCTGTATTGACCTTGTGAACCATTTCAAGTGCTCTTGCCCACCAGCCACTCGGGGTATGAAATCATCCTTATCCATTTTCCATTGCCCGGGTCCCCATTGCCTTAATGGTGGTCAGTGCATGGATAGGATTGGAGGCTACAGTTGTCGCTGCTTGCCTGGCTTTGCTGGGGAGCGTTGTGAGGGAGACATCAACGAGTGCCTCTCCAACCCCTGCAGCTCTGAGGGCAGCCTGGACTGTATACAGCTCACCAATGACTACCTGTGTGTTTGCCGTAGTGCCTTTACTGGTCGGCACTGTGAAACCTTCGTCGATGTGTGTCCCCAGATGCCCTGCCTGAATGGAGGGACTTGTGCTGTGGCCAGTAACATGCCTGATGGTTCATTTGCCGTTGTCCCCCAGGGATTTTCCGGGGCAAGGTGCCAGAGCAGCTGTGGACAAGTGAAATGTAGGAAGGGGGAGCAGTGTGTGCACACCGCCTCTGGACCCCGCTGCTTCTGCCCCAGTCCCCGGGACTGCCAGTCAGGCTGTGCCAGTAGCCCCTGCCAGCACGGGGGCAGCTGCCACCCTCAGCGCCAGCCTCCTTATTACTCCTGCCAGTGTGCCCCACCATTCTCGGGTAGCCGCTGTGAACTCTACACGCCACCCCCCAGCACCCCTCCTGCCACCTGTCTGAGCCAGTATTGTGCCGACAAAGCTCGGGATGGCGTCTGTGATGAGGCCTGCAACAGCCATGCCTGCCAGTGGGATGGGGGTGACTGTTCTCTCACCATGGAGAACCCCTGGGCCAACTGCTCCTCCCCACTTCCCTGCTGGGATTATATCAACAACCAGTGTGATGAGCTGTGCAACACGGTCGAGTGCCTGTTTGACAACTTTGAATGCCAGGGGAACAGCAAGACATGCAAGTATGACAAATACTGTGCAGACCACTTCAAAGACAACCACTGTGACCAGGGGTGCAACAGTGAGGAGTGTGGTTGGGATGGGCTGGACTGTGCTGCTGACCCTTCAAAGACGGGCGCAGAAGGTACCCTGGTTATTGTGGTATTGATGCCACCTGAACAACTGCTCCAGGATGCTCGCAGCTTCTTGCGGGCACTGGGTACCCTGCTCCACACCAACCTGCGCATTAAGCGGGACTCCCAGGGGGAACTCATGGTGTACCCCTATTATGGTGAGAAGTCAGCTGCTATGAAGAAACAGAGCATGACACGCAGATCCCTTCCTGGTGAACAAGAACAGGAGGTGGCTGGGTCTAAAGTCTTTCTGGAAATTGACAACCGCCAGTGTGTTCAAGACTCACACCACTGCTTCAAGAACACGGATGCAGCAGCAGCTCTCCTGGCCTCTCACGCCATACAGGGGACCCTGTCATACCCTCTTGTGTCTGTCGTCAGTGAGTCCCTGACTCCAGAACGCACTCAGCTCCTCTATCTCCTTGCTGTTGCTGTTGTCATCATTCTGTTTATTATTCTGCTGGGGGTAATCATGGCAAAACGAAAGCGTAAGCATGGCTCTCTCTGGCTGCCTGAAGGTTTCACTCTTCGCCGAGATGCAAGCAATCACAAGCGTCGTGAGCCAGTGGGACAGGATGCTGTGGGGCTGAAAAATCTCTCAGTGCAAGTCTCAGAAGCTAACCTAATTGGTACTGGAACAAGTGAACACTGGGTCGATGATGAAGGGCCCCAGCCAAAGAAAGTAAAGGCTGAAGATGAGGCCTTACTCTCAGAAGAAGATGACCCCATTGATCGACGGCCATGGACACAGCAGCACCTTGAAGCTGCAGACATCCGTAGGACACCATCCCTCGCTCTCACCCCTCCTCAGGCACAGCAGGAGGTGGATGTGTTAGATGTGAATGTCCGTGGCCCAGATGGCTGCACCCCATTGATGTTGGCTTCTCTCCGAGGAGGCAGCTCAGATTTGAGTGATGAAGATGAAGATGCAGAGGACTCTTCTGCTAACATCATCACAGACTTGGTCTACCAGGGTGCCAGCCTCCAGGCCCAGACAGACCGGACTGGTGAGATGGCCCTGCACCTTGCAGCCCGCTACTCACGGGCTGATGCTGCCAAGCGTCTCCTGGATGCAGGTGCAGATGCCAATGCCCAGGACAACATGGGCCGCTGTCCACTCCATGCTGCAGTGGCAGCTGATGCCCAAGGTGTCTTCCAGATTCTGATTCGCAACCGAGTAACTGATCTAGATGCCAGGATGAATGATGGTACTACACCCCTGATCCTGGCTGCCCGCCTGGCTGTGGAGGGAATGGTGGCAGAACTGATCAACTGCCAAGCGGATGTGAATGCAGTGGATGACCATGGAAAATCTGCTCTTCACTGGGCAGCTGCTGTCAATAATGTGGAGGCAACTCTTTTGTTGTTGAAAAATGGGGCCAACCGAGACATGCAGGACAACAAGGAAGAGACACCTCTGTTTCTTGCTGCCCGGGAGGGGAGCTATGAAGCAGCCAAGATCCTGTTAGACCATTTTCCCAATCGAGACATCACAGACCATATGGATCGTCTTCCCCGGGATGTGGCTCGGGATCGCATGCACCATGACATTGTGCGCCTTCTGGATGAATACAATGTGACCCCAAGCCCTCCAGGCACCGTGTTGACTTCTGCTCTCTCACCTGTCATCTGTGGGCCCAACAGATCTTTCCTCAGCCTGAAGCACACCCCAATGGGCAAGAAGTCTAGACGGCCCAGTGCCAAGAGTACCATGCCTACTAGCCTCCCTAACCTTGCCAAGGAGGCAAAGGATGCCAAGCGTAGTAGGAGGAAGAAGTCTCTGAGTGAGAAGGTCCAACTGTCTGAGAGTTCAGTAACTTTATCCCCTGTTGATTCCCTAGAATCTCCTCACACGTATGTTTCCGACACCACATCCTCTCCAATGATTACATCCCCTGGGATCTTACACGCCTCACCCAACCCTATGTTGGCCACTGCCGCCCCTCCTGCCCCAGTCCATGCCCAGCATGCACTATCTTTTTCTAACCTTCATGAAATGCAGCCTTTGGCACATGGGGCCAGCACTGTGCTTCCCTCAGTGAGCCAGTTGCTATCCCACCACCACATTGTGTCTCCAGGCAGTGGCAGTGCTGGAAGCTTGAGTAGGCTCCATCCAGTCCCAGTCCCAGCAGATTGGATGAACCGCATGGAGGTGAATGAGACCCAGTACAATGAGATGTTTCGTATGGTCCTGGCTCCAGCTGTAGGGCACCCATCCTGGCATAGCTCCCCAGAGAGGCCACCTGAAGGGAAGCACATAACCACCCCTCGGGAGCCCTTGCCCCCCATTGTGACTTTCCAGCTCATCCCTAAAGGCAGTATTGCCCAACCAGCGGGGGCTCCCCAGCCTCAGTCCACCTGCCCTCCAGCTGTTGCGGGCCCCCTGCCCACCATGTACCAGATTCCAGAAATGGCCCGTTTGCCCAGTGTGGCTTTCCCCACTGCCATGATGCCCCAGCAGGACGGGCAGGTAGCTCAGACCATTCTCCCAGCCTATCATCCTTTCCCAGCCTCTGTGGGCAAGTACCCCACACCCCCTTCACAGCACAGTTATGCTTCCTCAAATGCTGCTGAGCGAACACCCAGTCACAGTGGTCACCTCCAGGGTGAGCATCCCTACCTGACACCATCCCCAGAGTCTCCTGACCAGTGGTCAAGTTCATCACCCCACTCTGCTTCTGACTGGTCAGATGTGACCACCAGCCCTACCCCTGGGGGAGCTGGAGAGGTCAGCGGGGACCTGGGACACACATGTCTGAGCCACCACACAACAACATGCAGGTTTATGCGTGA

[0029] The disclosed MOL1a nucleotide encodes a protein which has 2469amino acid residues, referred to as the MOL1a protein. The MOL1a proteinwas analyzed for signal peptide prediction and cellular localization.SignalP results predict that MOL1a is cleaved between position 25 and 26(AHA-LQ) of SEQ ID NO:2. Psort and Hydropathy profiles also predict thatMOL1a contains a signal peptide and is likely to be localized in theplasma membrane (Certainty=0.4600). A disclosed MOL1a polypeptidesequence is presented in Table 1B using the one-letter amino acid code.TABLE 1B Encoded MOL1a protein sequence. (SEQ ID NO:2)MPALRPALLWALLALWLCCATPAHALQCRDGYEPCVNEGMCVTYHNGTGYCKCPEGFLGEYCQHRDPCEKNRCQNGGTCVAQAHLGKATCRCASGFTGEDCQYSTSHPCFVSRPCLNGGTCHMLSRDTYECTCQVGFTGKECQWTDACLSHPCANGSTCTTVANQFSCKCLTGFTGQKCETDVNECDIPGHCQHGGTCLNLPGSYQCQCPQGFTGQYCDSLYVPCAPSPCVNGGTCRQTGDFTFECHLPGFEGSTCERNIDDCPNHRCQNGGVCVDGVNTYNCRCPPQWTGQFCTEDVDECLLQPNACQNWGTCANRNGGYGCVCVNGWSGDDCSENIDDCAFGACTPGSTCIDRVASFSCMCPEGKAGLLCHLDDACISNPCHKGALCDTNPLNGQYICTCPQGYKGADCTEDVDECAMANSNPCEHAGKCVNTDGAFHCECLKGYAGPRCEMDINECHSDPCQNDATCLDKIGGFTCLCMPGFKGVHCELEINECQSNPCVNNGQCVDKVNRFQCLCPPGFTGPVCQIDIDDCSSTPCLNGAKCIDHPNGYECQCATGFTGVLCEENIDNCDPDPCHHGQCQDGIDSYTCICNPGYMGAICSDQIDECYSSPCLNDGRCIDLVNGYQCNCQPGTSGVNCEINFDDCASNPCIHGICMDGINRYSCVCSPGFTGQRCNIDIDECASNPCPKGATCINGVNGFRCICPEGPHHPSCYSQVNECLSNPCIHGNCTGGLSGYKCLCDAGWVGINCEVDKNECLSNPCQNGGTCDNLVNGYRCTCKKGFKGYNCQVNIDECASNPCLNQGTCFDDISGYTCHCVLPYTGKNCQTVLAPCSPNPCENAAVCKESPNFESYTCLCAPGWQGQRCTIDIDECISKPCMNHGLCHNTQGSYMCECPPGFSGMDCEEDIDDCLASPCQNGGSCMDGVNTFSCLCLPGFTGDKCQTDMNECLSEPCKNGGTCSDYVNSYTCKCQAGFDGVHCENNINECTESSCFNGGTCVDGINSFSCLCPVGFTGSFCLHEINECSSHPCLNDGTCVDGLGTYRCSCPLGYTGKNCQTLVNLCSRSPCKNKGTCVQKKAESQCLCPSGWAGAYCDVPNVSCDIAASRRGVLVEHLCQHSGVCINAGNTHYCQCFLGYTGSYCEEQLDECASNPCQHGATCSDFIGGYRCECVPGYQGVNCEYEVDECQNQPCQNGGTCIDLVNHFKCSCPPGTRGHKSSLSIFHCPGPECLNGGQCNDRIGGYSCRCLPGFAGERCEGDINECLSUPCSSEGSLDCIQLTNDYLCVCRSAFTGRHCETFVDVCPQMPCLNGGTCAVASNMPDGSFAVVPQGFSGARCQSSCGQVKCRKGEQCVHTASGPRCFCPSPRDCESGCASSPCQHGGSCHPQRQPPYYSCQCAPPFSGSRCELYTAPPSTPPATCLSQYCADKARDGVCDEACNSHACQWDGGDCSLTMENPWANCSSPLPCWDYINNQCDELCNTVECLFDNFECQGNSKTCKYDKYCADHFKDNHCDQGCNSEECGWDGLDCAADQPENLAEGTLVIVVLMPPEQLLQDARSFLRALGTLLHTNLRIKRDSQGELMVYPYYGEKSAAMKKQRMTRRSLPGEQEQEVAGSKVFLEIDNRQCVQDSDHCFKNTDAAAALLASHAIQGTLSYPLVSVVSESLTPERTQLLYLLAVAVVIILFIILLGVIMAKRKRKHGSLWLPEGFTLRRDASNHKRREPVGQDAVGLKNLSVQVSEANLIGTGTSEHWVDDEGPQPKKVKAEDEALLSEEDDPIDRRPWTQQHLEAADIRRTPSLALTPPQAEQEVDVLDVNVRGPDGCTPLMLASLRGGSSDLSDEDEDAEDSSANIITDLVYQGASLQAQTDRTGEMALHLAARYSRADAAKRLLDAGADANAQDNMGRCPLHAAVAADAQGVFQILIRNRVTDLDARMNDGTTPLILAARLAVEGMVAELINCQADVNAVDDHGKSALHWAAAVNNVEATLLLLKNGANRDMQDNKEETPLFLAAREGSYEAAKILLDHFANRDITDHMDRLPRDVARDRMHHDIVRLLDEYNVTPSPPGTVLTSALSPVICGPNRSFLSLKHTPMGKKSRRPSAKSTMPTSLPNLAKEAKDAKGSRRKKSLSEKVQLSESSVTLSPVDSLESPHTYVSDTTSSPMITSPGILQASPNPMLATAAPPAPVHAQHALSFSNLHEMQPLAHGASTVLPSVSQLLSHHHIVSPGSGSAGSLSRLHPVPVPADWMNRMEVNETQYNEMFGMVLAPAVGHPSWHSSPERPPEGKHITTPREPLPPIVTFQLIPKGSIAQPAGAPQPQSTCPPAVAGPLPTMYQIPEMARLPSVAFPTAMMPQQDGQVAQTILPAYHPFPASVGKYPTPPSQHSYASSNAAERTPSHSGHLQGEHPYLTPSPESPDQWSSSSFHSASDWSDVTTSPTPGGAGGGQRGPGTHMSEPPHNNMQVYA

[0030] A region of the MOL1a nucleic acid sequence has 6436 of 7416bases (86%) identical to a Rattus norvegicus Notch-like protein mRNA(GENBANK-ID:RATNOTCHX I acc:M93661), with an E-value of 0.0. In allBLAST alignments herein, the “E-value” or “Expect” value is a numericindication of the probability that the aligned sequences could haveachieved their similarity to the BLAST query sequence by chance alone,within the database that was searched. For example, the probability thatthe subject (“Sbjct”) retrieved from the MOL1a BLAST analysis, e.g., theRattus norvegicus Notch-like protein mRNA, matched the Query MOL1asequence purely by chance is 0.0. MOL1a also has 2443 of 2471 amino acidresidues (98%) positive with patp:AAY06816 Human Notch2 (humN2) proteinsequence—Homo sapiens, 2471 aa.

[0031] The Expect value is used as a convenient way to create asignificance threshold for reporting results. The default value used forblasting is typically set to 0.0001. In BLAST 2.0, the Expect value isalso used instead of the P value (probability) to report thesignificance of matches. For example, an E value of one assigned to ahit can be interpreted as meaning that in a database of the current sizeone might expect to see one match with a similar score simply by chance.An E value of zero means that one would not expect to see any matcheswith a similar score simply by chance. See, e.g.,http://www.ncbi.nlm.nih.gov/Education/BLASTinfo/.

[0032] Occasionally, a string of X's or N's will result from a BLASTsearch. This is a result of automatic filtering of the query forlow-complexity sequence that is performed to prevent artifactual hits.The filter substitutes any low-complexity sequence that it finds withthe letter “N” in nucleotide sequence (e.g., “NNNNNNNNNNNNN”) or theletter “X” in protein sequences (e.g., “XXXXXXXXX”). Low-complexityregions can result in high scores that reflect compositional bias ratherthan significant position-by-position alignment. Wootton and Federhen,Methods Enzymol 266:554-571, 1996.

[0033] Utilities for the MOLX nucleic acids and their encodedpolypeptides can be inferred based on the homology of the disclosed MOLXnucleic acids and/or polypeptides (including domains of the encodedpolypeptides) to previously described sequences.

[0034] MOL1a expression in different tissues was examined through TaqManas described below in Example 1.

[0035] MOL1a is expressed in at least the following tissues: kidney,brain, lymph node, muscle, hippocampus, bone marrow, placenta, thyroid,para-thyroid, prostate, testis, epidermis, ovary, coronary artery,liver, lung, spinal cord, stomach, breast, lung, uterus, and colon. Itis likely that Notch proteins are expressed in all tissues, so thewidespread expression of MOL1a agrees with its homology with Notch.

[0036] One or more consensus positions (Cons. Pos.) of the nucleotidesequence of MOL1a have been identified as single nucleotidepolymorphisms (SNPs) as shown in Table 1C. A dash (“-”), when shown,means that a base is not present. The sign “>” means “is changed to”.SNPs were identified using the techniques disclosed in Example 3. TABLE1C SNPs for MOL1a AA Consensus Base change Position Change PositionResidue Change 4288 G > A 1429 A > T 5858 T > C 1952 L > P 5833 A > G1944 T > A 5366 C > T 1788 T > I

[0037] MOL1b

[0038] MOL1a was subjected to the exon linking process to confirm thesequence. PCR primers were designed by starting at the most upstreamsequence available, for the forward primer, and at the most downstreamsequence available for the reverse primer. In each case, the sequencewas examined, walking inward from the respective termini toward thecoding sequence, until a suitable sequence that is either unique orhighly selective was encountered, or, in the case of the reverse primer,until the stop codon was reached. Such primers were designed based on insilico predictions for the full length cDNA, part (one or more exons) ofthe DNA or protein sequence of the target sequence, or by translatedhomology of the predicted exons to closely related human sequencessequences from other species. These primers were then employed in PCRamplification based on the following pool of human cDNAs: adrenal gland,bone marrow, brain—amygdala, brain—cerebellum, brain—hippocampus,brain—substantia nigra, brain—thalamus, brain—whole, fetal brain, fetalkidney, fetal liver, fetal lung, heart, kidney, lymphoma—Raji, mammarygland, pancreas, pituitary gland, placenta, prostate, salivary gland,skeletal muscle, small intestine, spinal cord, spleen, stomach, testis,thyroid, trachea, uterus. Usually the resulting amplicons were gelpurified, cloned and sequenced to high redundancy. The resultingsequences from all clones were assembled with themselves, with otherfragments in CuraGen Corporation's database and with public ESTs.Fragments and ESTs were included as components for an assembly when theextent of their identity with another component of the assembly was atleast 95% over 50 bp. In addition, sequence traces were evaluatedmanually and edited for corrections if appropriate. These proceduresprovide the sequence reported below, which is designated MOL1b, oralternatively Accession Number CG56250-02. This differs from thepreviously identified sequence in lacking 996 internal amino acids inaddition to a few minor changes.

[0039] A disclosed Notch-like nucleic acid of 6728 nucleotides, MOL1b,is shown in Table 1C. The disclosed MOL1b open reading frame (“ORF”)begins at the ATG initiation codon at nucleotides 13-15, and terminatesat a TGA codon at nucleotides 4431-4434. In Table 1D the start and stopcodons are in bold letters, and the untranslated regions are underlined.TABLE 1D MOL1b nucleotide sequence. (SEQ ID NO:3) TCATCTGGAATTATGCCCGCCCTGCGCCCCGCTCTGCTGGGCGCTGCTGGCGCTCTGGCTGTGCTCGCGGCCCCCGCGCATGCATTGCAGTGTCGAGATGGCTATGAACCCTGTGTAAATGAAGGAATGTGTGTTACCTACCACAATGGCACAGGATACTGCAAATGTCCAGAAGGCTTCTTGGGGGAATATTGTCAACATCGAGACCCCTGTGAGAAGAACCGCTCCCAGAATGGTGGGACTTGTGTGGCCCAGGCCATGCTGGGGAAAGCCACGTGCCGATGTGCCTCAGGGTTTACAGGAGAGGACTGCCAGTACTCAACATCTCATCCATGCTTTGTGTCTCGACCCTGCCTGAATGGCGGCACATGCCATATGCTCAGCCGGGATACCTATGAGTGCACCTGTCAAGTCGGGTTTACAGGTAAGGAGTGCCAATGGACGGATGCCTGCCTGTCTCATCCCTGTGCAAATGGAAGTACCTGTACCACTGTGGCCAACCAGTTCTCCTGCAAATGCCTCACAGGCTTCACAGGGCAGAAATGTGAGACTGATGTCAATGAGTGTGACATTCCAGGACACTGCCAGCATGGTGGCACCTGCCTCAACCTGCCTGGTTCCTACCAGTGCCAGTGCCCTCAGGGCTTCACAGGCCAGTACTGTGACAGCCTGTATGTGCCCTGTGCACCCTCACCTTGTGTCAATGGAGGCACCTGTCGGCAGACTCGTGACTTCACTTTTGAGTGCAACTCCCTTCCAGGTTTTGAAGGGAGCACCTGTGAGAGGAATATTGATGACTGCCCTAACCACAGGTGTCAGAATGGAGGGGTTTGTGTGGATGGGGTCAACACTTACAACTGCCGCTGTCCCCCACAATGGACAGGACAGTTCTGCACAGAGGATGTGGATGAATGCCTGCTGCAGCCCAATGCCTGTCAAAATGGGGGCACCTGTGCCAACCGCAATGGAGGCTATGGCTGTGTATGTGTCAACGGCTGGAGTGGAGATGACTGCAGTGAGAACATTGATGATTGTGCCTTCGCCTCCTGTACTCCAGGCTCCACCTGCATCGACCGTGTGGCCTCCTTCTCTTGCATGTGCCCAGAGGGAAGGCAGGTCTCCTGTGTCATCTGGATGATGCATGCATCAGCCAATCCTTGCCACAAGGGGGCACTGTGTGACACCAACCCCCTAAATGGGCAATATATTTGCACCTGCCCACAAGGCTACAAAGGGGCTGACTGCACAGAAGATGTGGATGAATGTGCCATGGCCAATAGCAATCCTTGTGAGCATGCAGGAAAATGTGTGAACACGGATGGCGCCTTCCACTGTGAGTGTCTGAAGGGTTATGCAGGACCTCGTTGTGAGATGGACATCAATGAGTGCCATTCAGACCCCTGCCAGAATGATGCTACCTGTCTGGATGGGATTGGAGGCTTCACATGTCTGTGCATGCCAGGTTTCAAAGGTGTGCATTGTGAATTAGAAATAAATGAATGTCAGAGCAACCCTTGTGAACAATGGGCAGAGTGTGTGGATAAAGTCAAPCGTTTCCAGTGCCTGTGTCCTCCTGGTTTCACTGGGCCAGTTTGCCAGATTGATATTGATGACTGTTCCAGTACTCCGTGTCTGAATGGGGCAAAGTGTATCGATCACCCGAATGGCTATGAATGCCAGTGTGCCACAGGTTTCACTGGTGTGTTGTGTGAGGAGAACATTGACAACTGTGACCCCGATCCTTGCCACCATGGTCAGTGTCAGGATGGTATTGATTCCTACACCTGCATCTGCAATCCCGGGTACATGGGCGCCATCTGCAGTGACCAGATTGATGAATGTTACAGCAGCCCTTGCCTGAACGATGGTCGCTGCATTGACCTGGTCAATGGCTACCAGTGCAACTGCCAGCCAGGCACGTCACCCCTTAATTGTGAAATTAATTTTGATGACTGTGCAAGTAACCCTTGTATCCATGGAATCTGTATGGATGGCATTAATCGCTACACTTGTGTCTGCTCACCAGGATTCACAGGGCAGAGATGTAACATTGACATTGATGAGTGTGCCTCCAATCCCTGTCGCAAGGGTGCAACATGTATCAACGGTGTGAATGGTTTCCGCTGTATATGCCCCGAGGGACCCCATCACCCCAGCTGCTACTCACAGGTGAACGAATGCCTGAGCAATCCCTGCATCCATGGAAACTGTACTGGAGGTCTCAGTGGATATAAGTGTCTCTGTGATGCAGGCTGGGTTGGCATCAACTGTGAAGTGGACAAAAATGAATGCCTTTCGAATCCATGCCAGAATGGAGGAACTTGTGACAATCTGGTGAATGGATACAGGTGTACTTGCAAGAAGGGCTTTAAAGGCTATAACTGCCAGGTGAATATTGATGAATGTGCCTCAAATCCATGCCTGAACCAAGGAACCTGCTTTGATGACATAAGTGGCTACACTTGCCACTGTGTGCTGCCATACACAGGCAAGAATTGTCAGACAGTATTGGCTCCCTGTTCCCCAAACCCTTGTGAGAATGCTGCTGTTTGCAAAGAGTCACCAAATTTTGAGAGTTATACTTGCTTGTGTGCTCCTGGCTGGCAAGGTCAGCGGTGTACCATTGACATTGACGAGTGTATCTCCAAGCCCTGCATGAACCATGGTCTCTGCCATAACACCCAGGGCAGCTACATGTGTGAATGTCCACCAGGCTTCAGTGGTATGGACTGTGAGGAGGACATTGATGACTGCCTTGCCAATCCTTGCCAGAATGGAGGTTCCTGTATGGATCGAGTGAATACTTTCTCCTGCCTCTGCCTTCCGGGTTTCACTGGGGATAAGTGCCAGACAGACATGAATGAGTGTCTGAGTGAACCCTGTAAGAATGGAGGGACCTGCTCTGACTACGTCAACAGTTACACTTGCAAGTGCCAGGCAGGATTTGATGGAGTCCATTGTGAGAACAACATCAATGAGTGCACTGAGAGCTCCTGTTTCAATGGTGGCACATGTGTTGATGGGATTAACTCCTTCTCTTGCTTGTGCCCTGTGGGTTTCACTGGATCCTTCTGCCTCCATGAGATCAATGAATGCAGCTCTCATCCATGCCTGAATGAGGGAACGTGTGTTGATGGCCTGGGTACCTACCGCTGCAGCTGCCCCCTGGGCTACACTGGGAAAAACTGTCAGACCCTGGTGAATCTCTGCAGTCGGTCTCCATGTAAAAACAAAGGTACTTGTGTTCACAAAAAAGCAGAGTCCCAGTGCCTATGTCCATCTGGATGGGCTGGTGCCTATTGTGACGTGCCCAATGTCTCTTGTGACATAGCAGCCTCCAGGAGAGGTGTGCTTGTTGAACACTTGTGCCACCACTCAGGTGTCTGCATCAATGCTGGCAACACGCATTACTGTCAGTGCCCCCTGGGCTATACTGGGAGCTACTGTGAGGAGCAACTCGATGAGTGTGCGTCCAACCCCTGCCAGCACGGGGCAACATCCAGTGACTTCATTGGTGGATACAGATGCGAGTGTGTCCCAGGCTATCAGGGTGTCAACTGTGAGTATGAAGTGGATGAGTGCCAGAATCAGCCCTGCCAGAATGGAGGCACCTGTATTGACCTTGTGAACCATTTCAAGTGCTCTTGCCCACCAGGCACTCGGGGCCTACTCTGTGAAGAGAACATTGATGACTGTGCCCGGGGTCCCCATTGCCTTAATGGTGGTCAGTGCATGGATAGGATTGGAGGCTACAGTTGTCGCTGCTTGCCTGGCTTTGCTGGGGAGCGTTGTGAGGGAGACATCAACGAGTGCCTCTCCAACCCCTGCAGCTCTGAGGGCAGCCTGGACTGTATACAGCTCACCAATGACTACCTGTGTGTTTGCCGTAGTGCCTTTACTGGCCGGCACTGTGAAACCTTCGTCGATGTGTGTCCCCAGATGCCCTGCCTGAATGGAGGGACTTGTGCTGTGGCCAGTAACATGCCTGATGGTTTCATTTGCCGTTGTCCCCCGGGATTTTCCGGGGCAAGGTACCAGATTCCAGAAATGGCCCGTTTGCCCAGTGTGGCTTTCCCCACTGCCATGATGCCCCAGCAGGACGGGCAGGTAGCTCAGACCATTCTCCCAGCCTATCATCCTTTCCCAGCCTCTGTGGGCAAGTACCCCACACCCCCTTCACAGCACAGTTATGCTTCCTCAAATGCTGCTGAGCGAACACCCAGTCACAGTGGTCACCTCCAGGGTGACCATCCCTACCTGACACCATCCCCAGAGTCTCCTGACCAGTGGTCAAGTTCATCACCCCACTCTGCTTCTGACTGGTCAGATGTGACCACCAGCCCTACCCCTGGGGGTGCTGGAGGAGGTCAGCGGGGACCTGGGACACACATGTCTGAGCCACCACACAACAACATGCAGGTTTATGCGTGAGAGAGTCCACCTCCAGTGTAGAGACATAACTGACTTTTGTAAATGCTGCTGAGGAACAAATGAAGGTCATCCGGGAGAGAAATGAAGAAATCTCTGGAGCCAGCTTCTAGAGGTAGGAAAGAGAAGATGTTCTTATTCAGATAATGCAAGAGAAGCAATTCGTCAGTTTCACTGGGTATCTGCSSGGCTTATTGATTATTCTAATCTAATAAGACAAGTTTGTGGAAATGCAAGATGAATACAAGCCTTGGGTCCATGTTTACTCTCTTCTATTTGGAGAATAAGATGGATGCTTATTGAAGCCCAGACATTCTTGCAGCTTGGACTGCATTTTAAGCCCTGCAGGCTTCTGCCATATCCATGAGAAGATTCTACACTAGCGTCCTGTTCGGAATTATGCCCTGGAATTCTGCCTGAATTGACCTACGCATCTCCTCCTCCTTGGACATTCTTTTGTCTTCATTTGGTGCTTTTGGTTTTGCACCTCTCCGTGATTGTAGCCCTACCAGCATGTTATAGGGCAAGACCTTTGTGCTTTTGATCATTCTGGCCCATGAAAGCAACTTTGGTCTCCTTTCCCCTCCTGTCTTCCCGGTATCCCTTGGAGTCTCACAAGGTTTACTTTGGTATGGTTCTCAGCACAAACCTTTCAAGTATGTTGTTTCTTTGGAAAATGGACATACTGTATTGTGTTCTCCTGCATATATCATTCCTGGAGAGAGAAGGGGAGAAGAATACTTTTCTTCAACAAATTTTGGGGGCAGGAGATCCCTTCAAGAGGCTGCACCTTAATTTTTCTTGTCTGTGTGCAGGTCTTCATATAAACTTTACCAGGAAGAAGGGTGTGAGTTTGTTGTTTTTCTGTGTATGGGCCTGGTCAGTGTAAAGTTTTATCCTTGATAGTCTAGTTACTATGACCCTCCCCACTTTTTTAAAACCAGAAAAAGGTTTGGAATGTTGGAATGACCAAGAGACAAGTTAACTCGTGCAAGAGCCAGTTACCCACCCACAGGTCCCCCTACTTCCTGCCAAGCATTCCATTGACTGCCTGTATGGAACACATTTGTCCCAGATCTGAGCATTCTAGGCCTGTTTCACTCACTCACCCAGCATATGAAACTAGTCTTAACTGTTGAGCCTTTCCTTTCATATCCACAGAAGACACTGTCTCAAATGTTGTACCCTTGCCATTTACGACTGAACTTTCCTTAGCCCAAGGGACCCAGTGACAGTTGTCTTCCGTTTGTCAGATGATCAGTCTCTACTGATTATCTTGCTGCTTAAAGGCCTGCTCACCAATCTTTCTTTCACACCGTGTGGTCCGTGTTACTGGTATACCCAGTATGTTCTCACTGAAGACATGGACTTTATATGTTCAAGTGCAGGAATTGGAAAGTTGGACTTGTTTTCTATGATCCAAAACAGCCCTATAAGAAGGTTGGAAAAGGAGGAACTATATAGCAGCCTTTGCTATTTTCTGCTACCATTTCTTTTCCTCTGAAGCGGCCATGACATTCCCTTTGGCAACTAACGTAGAAACTCAACAGAACATTTTCCTTTCCTAGAGTCACCTTTTAGATGATAATGGACAACTATAGACTTGCTCATTGTTCAGACTGATTGCCCCTCACCTGAATCCACTCTCTGTATTCATGCTCTTGGCAATTTCTTTGACTTTCTTTTAAGGGCAGAAGCATTTTAGTTAATTGTAGATAAAGAATAGTTTTCTTCCTCTTCTCCTTGGGCCAGTTAATAATTGGTCCATGGCTACACTGCAACTTCCGTCCAGTGCTGTGATGCCCATGACACCTGCAAAATAAGTTCTGCCTGGGCATTTTGTAGATATTAACAGGTGAATTCCCGACTCTTTTGGTTTGAATGACAGTTCTCATTCCTTCTATGCTCCAAGTATGCATCAGTGCTTCCCACTTACCTGATTTGTCTGTCGGTGGCCCCCATATGGAAACCCTGCGTGTCTGTTGGCATAATAGTTTACAAATGGTTTTTTCAGTCCTATCCAAATTTATTGAACCAACAAAAATAATTACTTCTGCCCTGAGATAAGCAGATTAAGTTTGTTCATTCTCTGCTTTATTCTCTCCATGTGGCAACATTCTGTCAGCCTCTTTCATAGTGTGCAAACATTTTATCATTCTAAATGGTGACTCTCTGCCCTTGGACCCATTTATTATTCACAGATGGGGAGAACCTATCTGCATGGACCCTCACCATCCTCTGTGCAGCACACACAGTGCAGGGAGCCAGTGGCGATGGCGATGACTTTCTTCCCCTGG

[0040] The protein encoded by the MOL1b nucleic acid sequence has 2469amino acid residues, and is disclosed in Table 1E. The MOL1b protein wasanalyzed for signal peptide prediction and cellular localization.SignalP results predict that MOL1b is cleaved between position 25 and 26(AHA-LQ) of SEQ ID NO:4. Psort and Hydropathy profiles also predict thatMOL1b contains a signal peptide and is likely to be localizedextracellularly (Certainty=0.7666). TABLE 1E Encoded MOL1b proteinsequence. (SEQ ID NO:4)MPALRPALLWALLALWLCCAAPAHALQCRDGYEPCVNEGMCVTYHNGTCYCKCPEGFLGEYCQHRDPCEKNRCQNGGTCVAQAMLGKATCRCASGFTGEDCQYSTSHPCFVSRPCLNGGTCHMLSRDTYECTCQVGFTGKECQWTDACLSHPCANCSTCTTVANQFSCKCLTGFTGQKCETDVNECDTPCHCQHGGTCLNLPGSYQCQCPQGFTGQYCDSLYVPCAPSPCVNGGTCRQTGDFTFECNCLPGFEGSTCERNIDDCPNHRCQNGGVCVDGVNTYNCRCPPQWTGQFCTEDVDECLLQPNACQNGGTCANRNGGYGCVCVNGWSGDDCSENIDDCAFASCTPGSTCIDRVASFSCMCPECKAGLLCHLDDACISNPCHKGALCDTNPLNGQYICTCPQGYKGADCTEDVDECAMANSNPCEHAGKCVNTDGAFHCECLKGYAGPRCEMDINECHSDPCQNDATCLDKIGGFTCLCMPGFKGVHCELEINECQSNPCVNNCQCVDKVNRFQCLCPPGFTGPVCQIDIDDCSSTPCLNGAKCIDHPNGYECQCATGFTCVLCEENIDNCDPDPCHHGQCQDGIDSYTCICNPGYMGAICSDQIDECYSSPCLNDGRCIDLVNGYQCNCQPGTSGVNCEINFDDCASNPCIHGICMDGINRYSCVCSPGFTGQRCNIDIDECASNPCRKGATCINGVNGFRCICPEGPHHPSCYSQVNECLSNPCIHGNCTGGLSGYKCLCDAGWVGINCEVDKNECLSNPCQNGGTCDNLVNGYRCTCKKGFKGYNCQVMIDECASNPCLNQGTCFDDISGYTCHCVLPYTGKNCQTVLAPCSPNPCENAAVCKESPNFESYTCLCAPGWQGQRCTIDIDECISKPCMNHGLCHNTQGSYMCECPPGFSGMDCEEDIDDCLANPCQNGGSCMDGVNTFSCLCLPGFTGDKCQTDMNECLSEPCKNCGTCSDYVNSYTCKCQAGFDGVHCENNINECTESSCFNCGTCVDGINSFSCLCPVGFTGSFCLHEINECSSHPCLNEGTCVDGLGTYRCSCFLGYTGKNCQTLVNLCSRSPCKNKGTCVQKKAESQCLCPSGWAGAYCDVPNVSCDIAASRRGVLVEHLCQHSGVCINAGNTHYCQCPLGYTGSYCEEQLDECASNPCQHGATCSDFIGGYRCECVPCYQGVNCEYEVDECQNQPCQNGGTCIDLVNHFKCSCPPGTRGLLCEENIDDCARGPHCLNGCQCMDRIGGYSCRCLPGFAGERCEGDINECLSNPCSSEGSLDCIQLTNDYLCVCRSAFTGRHCETFVDVCPQMPCLNGGTCAVASNMPDGFTCRCPPGFSGARYQIPEMARLPSVAFPTAMMPQQDGQVAQTILPAYHPFPASVGKYPTPPSQHSYASSNAAERTPSHSGHLQGEHPYLTPSPESPDQWSSSSPHSASDWSDVTTSPTPGGAGGGQRGPGTHMSEPPHNNMQVYA

[0041] A region of the MOL1b nucleic acid sequence, localized tochromosome 1, has 4041 of 4042 bases (99%) identical to agb:GENBANK-ID:AF308601lacc:AF308601.1 mRNA from Homo sapiens (Homosapiens NOTCH 2 (N2) mRNA, complete cds), with an E-value of 0.0.

[0042] The amino acid sequence of MOL1b has 1340 of 1343 amino acidresidues (99%) identical to, and 1340 of 1343 amino acid residues (99%)similar to, the 2471 amino acid residue ptnr:TREMBLNEW-ACC:AAG37073protein from Homo sapiens (Human) (NOTCH2 PROTEIN).

[0043] MOL1b expressed in at least the following tissues: adrenal gland,bone marrow, brain—amygdala, brain—cerebellum, brain—hippocampus,brain—substantia nigra, brain—thalamus, brain—whole, fetal brain, fetalkidney, fetal liver, fetal lung, heart, kidney, lymphoma—Raji, mammarygland, pancreas, pituitary gland, placenta, prostate, salivary gland,skeletal muscle, small intestine, spinal cord, spleen, stomach, testis,thyroid, trachea, uterus, Aorta, Ascending Colon, Bone, Cartilage,Cochlea, Colon, Coronary Artery, Epidermis, Foreskin, Liver, Lung, Lymphnode, Lymphoid tissue, Muscle, Nasoepithelium, Ovary, Parathyroid Gland,Parotid Salivary glands, Peripheral Blood, Respiratory Bronchiole,Retina, Synovium/Synovial membrane, Thymus, Tonsils, Umbilical Vein,Vein, Whole Organism.

[0044] One or more consensus positions (Cons. Pos.) of the nucleotidesequence of MOL1b have been identified as single nucleotidepolymorphisms (SNPs) as shown in Table 1F. “Depth” represents the numberof clones covering the region of the SNP. The Putative Allele Frequency(PAF) is the fraction of all the clones containing the SNP. A dash(“-”), when shown, means that a base is not present. The sign “>” means“is changed to”. TABLE 1F SNPs for MOL1b Consensus Base Position DepthChange PAF 100 24 T > C 0.083 204 23 G > A 0.087 369 23 G > A 0.087

[0045] The amino acid sequence of MOL1a also had high homology to otherproteins as shown in table 1G. TABLE 1G BLAST results for MOL1a GeneIndex/ Protein/ Length Identity Positives Identifier Organism (aa) (%)(%) Expect gi|104252|pir||A3 Notch protein - 2524 1323/2515 1676/25150.0 5844 African clawed (52%) (66%), frog >gi|6679096|ref|N Notch gene2318  665/1515  860/1515 0.0 p_032742.1| homolog 3, (43%) (55%)(Drosophila) [Mus musculus] gi|13242247|ref|N Notch gene 2471 2251/24722340/2472 0.0 P_077334.1 homolog 2, (91%) (94%) (Drosophila) [Rattusnorvegicus] gi|2209059|dbj|BA Notch 2 2447 1240/2203 1546/2203 0.0A20535.1| [Takifugu (56%) (69%) rubripes] gi|6093542|sp|Q07 NEUROGENIC2531 1340/2538 1683/2538 0.0 008|NTC1_RAT LOCUS NOTCH (52%) (65%)HOMOLOG PROTEIN 1 PRECURSOR

[0046] A ClustalW analysis comparing disclosed proteins of the inventionwith related OR protein sequences is given in Table 1H, with MOL1a shownon line 1 and MOL1b on line 2.

[0047] In the ClustalW alignment of the MOL1a and MOL1b proteins, aswell as all other ClustalW analyses herein, the black outlined aminoacid residues indicate regions of conserved sequence (i.e., regions thatmay be required to preserve structural or functional properties),whereas non-highlighted amino acid residues are less conserved and canpotentially be mutated to a much broader extent without altering proteinstructure or function. Residue differences between any MOLX variantsequences herein are written to show the residue in the “a” variant andthe residue position with respect to the “a” variant. MOL residues inall following sequence alignments that differ between the individual MOLvariants are highlighted with a box and marked with the (o) symbol abovethe variant residue in all alignments herein.

[0048] When the sequences of the invention are referred to as MOL1, thisrefers to the sequences disclosed as MOL1a and MOL1b.

[0049] The presence of identifiable domains in MOL1, as well as allother MOLX proteins, was determined by searches using softwarealgorithms such as PROSITE, DOMAIN, Blocks, Pfam, ProDomain, and Prints,and then determining the Interpro number by crossing the domain match(or numbers) using the Interpro website (http:www.ebi.ac.uk/interpro).DOMAIN results, e.g., for MOL1 as disclosed in Table 1I, were collectedfrom the Conserved Domain Database (CDD) with Reverse Position SpecificBLAST analyses. This BLAST analysis software samples domains found inthe Smart and Pfam collections. For Table 1I and all successive DOMAINsequence alignments, fully conserved single residues are indicated byblack shading and “strong” semi-conserved residues are indicated by greyshading. The “strong” group of conserved amino acid residues may be anyone of the following groups of amino acids: STA, NEQK, NHQK, NDEQ, QHRK,MILV, MILF, HY, FYW.

[0050] Tables 1I-1N list the domain description from DOMAIN analysisresults against MOL1. The region from amino acid residue 1416 through1454 (SEQ ID NO:2) most probably (E=1e⁻⁶) contains a domain found inNotch and Lin-12, aligned here in table 1I. Notch and Lin-12 are bothinvolved in organismal development, cell cycle, and apoptosis. Theregion from amino acid residue 1504 through 1532 (SEQ ID NO:2) mostprobably (E=2e⁴) also contains a domain found in Notch and Lin-12,aligned here in table 1J. The region from amino acid residue 1875through 1906 (SEQ ID NO:2) most probably (E=6e-⁻⁵) contains an Ankrepeat, aligned here in table 1K. Ank repeats are markers for theprotein ankyrin which is involved in cell adhesion and contactinhibition. The region from amino acid residue 1974 through 2006 (SEQ IDNO:2) most probably (E=2e⁻⁴) also contains an Ank repeat, aligned herein table 1L. The region from amino acid residue 182 through 215 (SEQ IDNO:2) most probably (E=1e⁻⁴) contains a Calcium binding EGF-like domain,aligned here in table 1M. EGF is a growth factor that modulates theproliferation of many cell types. The region from amino acid residue 872through 908 (SEQ ID NO:2) most probably (E=9e⁻⁴) also contains a Calciumbinding EGF-like domain, aligned here in table 1N. This indicates thatthe MOL1 sequence has properties similar to those of other proteinsknown to contain these domains.

[0051] Uses of the Compositions of the Invention

[0052] The protein similarity information, expression pattern, cellularlocalization, and map location for the protein and nucleic aciddisclosed herein suggest that MOL1 may have important structural and/orphysiological functions characteristic of the EGF-like domain containingprotein family. Therefore, the nucleic acids and proteins of theinvention are useful in potential diagnostic and therapeuticapplications and as a research tool. These include serving as a specificor selective nucleic acid or protein diagnostic and/or prognosticmarker, wherein the presence or amount of the nucleic acid or theprotein are to be assessed. These also include potential therapeuticapplications such as the following: (i) a protein therapeutic, (ii) asmall molecule drug target, (iii) an antibody target (therapeutic,diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic aciduseful in gene therapy (gene delivery/gene ablation), (v) an agentpromoting tissue regeneration in vitro and in vivo, and (vi) abiological defense weapon.

[0053] The MOL1 nucleic acids and proteins have applications in thediagnosis and/or treatment of various diseases and disorders. Forexample, the compositions of MOL1 may have efficacy for the treatment ofpatients suffering from endometriosis, fertility disorders, cancer,hypercoagulation, idiopathic thrombocytopenic purpura,immunodeficiencies, systemic lupus erythematosus, asthma, emphysema,scleroderma, allergy, ARDS, Von Hippel-Lindau (VHL) syndrome,Alzheimer's disease, stroke, tuberous sclerosis, hypercalceimia,Parkinson's disease, Huntington's disease, cerebral palsy, epilepsy,multiple sclerosis, ulcers, ataxia-telangiectasia, leukodystrophies,behavioral disorders, addiction, anxiety, pain, neuroprotection,osteoporosis, hypercalceimia, arthritis, ankylosing spondylitis,scoliosis, diabetes, autoimmune disease, myasthenia gravis, musculardystrophy, renal artery stenosis, interstitial nephritis,glomerulonephritis, polycystic kidney disease, systemic lupuserythematosus, renal tubular acidosis, IgA nephropathy, hypercalceimia,Lesch-Nyhan syndrome, developmental disorders, growth disorders, and/orwounds, as well as other diseases, disorders and conditions. Thereactivation of the Notch signaling pathway during wound healing hasbeen demonstrated and the similarity between developmental andregenerative processes has been suggested (Exp Cell Res Feb. 1,1999;246(2):312-8).

[0054] These materials are further useful in the generation ofantibodies that bind immuno-specifically to the novel MOL1 substancesfor use in therapeutic or diagnostic methods. These antibodies may begenerated according to methods known in the art, using prediction fromhydrophobicity charts, as described in the “Anti-MOLX Antibodies”section below. The disclosed MOL1protein has multiple hydrophilicregions, each of which can be used as an immunogen. In one embodiment, acontemplated MOL1 epitope is from about amino acids 10 to 150. Inanother embodiment, a MOL1 epitope is from about amino acids 160 to 190.In additional embodiments, MOL1 epitopes are from about amino acids 195to 350, 400 to 525, 550 to 575, 590 to 600, 610 to 650, 780 to 880, 900to 1000, 1100 to 1150, 1175 to 1200, 1225 to 1300, and from about aminoacids 1380 to 1500. These novel proteins can also be used to developassay systems for functional analysis.

[0055] MOL2

[0056] MOL2 is a novel insulin-like growth factor binding protein-likeprotein. The novel nucleic acid of 2631 nucleotides, (SC98428706_EXT,SEQ ID NO:5) encoding a novel insulin-like growth factor bindingprotein-like protein is shown in Table 2A. The start and stop codons arein bold. TABLE 2A MOL2 Nucleotide Sequence (SEQ ID NO:5)ATGATTTACATACAAGTAATTTTTCAAGTAATGACCATTGAAAAAATGTTTTCTTTTTATTTTTTAGATTATTTCTCTTTATTCAGAAGCATACAGTTGTTTGCTGATTGCAAGAAGATGTTTCTGTGGCTGTTTCTGATTTTGTCAGCCCTGATTTCTTCGACAAATGCAGATTCTGACATATCGGTGGAAATTTGCAATGTGTGTTCCTGCGTGTCAGTTGAGAATGTGCTCTATGTCAACTGTGAGAAGGTTTCAGTCTACAGACCAAATCAGCTGAAACCACCTTGGTCTAATTTTTATCACCTCAATTTCCAAAATAATTTTTTAAATATTCTGTATCCAAATACATTCTTGAATTTTTCACATGCAGTCTCCCTGCATCTGGGGAATAATAAACTGCAGAACATTGAGGGAGGAGCCTTTCTTGGGCTCAGTGCATTAAAGCAGTTGCACTTGAACAACAATGAATTAAAGATTCTCCGAGCTGACACTTTCCTTGGCATAGAGAACTTGGAGTATCTCCAGGCTGACTACAATTTAATCAAGTATATTGAACGAGGAGCCTTCAATAAGCTCCACAAACTGAAAGTTCTCATTCTTAATGACAATCTGATTTCATTCCTTCCTGATAATATTTTCCGATTCGCATCTTTGACCCATCTGGATATACGAGGGAACAAGATCCAGAAGCTCCCTTATATCGGGGTTCTGGAACACATTGGCCGTGTCGTTGAATTGCAACTGGAAGATAACCCTTGGAACTGTAGCTGTGATTTATTGCCCTTAAAAGCTTGGCTGGAGAACATGCCATATAACATTTACATAGGAGAAGCTATCTGTGAAACTCCCAGTGACTTATATGGAAGGCTTTTAAAAGAAACCAACAAACAAGAGCTATGTCCCATGGGCACCGGCAGTGATTTTGACGTGCGCATCCTGCCTCCATCTCAGCTGGAAAATGGCTACACCACTCCCAATGGTCACACTACCCAAACATCTTTACACAGATTAGTAACTAAACCACCAAAAACAACAAATCCTTCCAAGATCTCTGGAATCGTTGCAGGCAAAGCCCTCTCCAACCGCAATCTCAGTCAGATTGTGTCTTACCAAACAAGGGTGCCTCCTCTAACACCTTGCCCGGCACCTTGCTTCTGCAAAACACACCCTTCAGATTTGGGACTAAGTGTGAACTGCCAAGAGAAAAATATACAGTCTATGTCTGAACTGATACCGAAACCTTTAAATGCGAAGAAGCTGCACGTCAATGGCAATAGCATCAAGGATGTGGACGTATCAGACTTCACTGACTTTGAAGGACTGGATTTGCTTCATCTAGGCAGCAATCAAATTACAGTGATTAAGGGAGACGTATTTCACAATCTCACTAATTTACGCACGCTATATCTCAATGGCAATCAAATTGAGAGACTCTATCCTGAAATATTTTCAGGTCTTCATAACCTGCAGTATCTGTATTTGGAATACAATTTGATTAAGGAAATCTCAGCAGGCACCTTTGACTCCATGCCAAATTTGCAGTTACTGTACTTAAACAATAATCTCCTAAAGAGCCTGCCTGTTTACATCTTTTCCGGAGCACCCTTAGCTAGACTGAACCTGAGGAACAACAAATTCATGTACCTGCCTGTCAGTGGCGTCCTTGATCAGTTGCAATCTCTTACACAGATTGACTTGGAGGGCAACCCATGGGACTGTACTTGTGACTTGGTGGCATTAAAGCTGTGGGTGGAGAAGTTGAGCGACGCGATTGTTGTGAAAGAACTGAAATGTGAGACGCCTGTTCAGTTTGCCAACATTGAACTGAAGTCCCTCAAAAATGAAATCTTATGTCCCAAACTTTTAAATAACCCGTCTGCACCATTCACAAGCCCTGCACCTGCCATTACATTCACCACTCCTTTGGGTCCCATTCGAAGTCCTCCTGGTCGGCCAGTGCCTCTGTCTATTTTAATCTTAAGTATCTTAGTGGTCCTCATTTTAACGGTGTTTGTTGCTTTTTGCCTTCTTGTTTTTGTCCTGCGACGCAACAAGAAACCCACAGTGAAGCACGAAGGCCTCGGGAATCCTGACTGTCGCTCCATGCAGCTGCAGCTAAGGAAGCATGACCACAAAACCAATAAAAAAGATGGACTGAGCACAGAAGCTTTCATTCCACAAACTATAGAACAGATGAGCAAGAGCCACACTTGTGGCTTGAAAGAGTCAGAAACTGGGTTCATGTTTTCAGATCCTCCAGGACAGAAAGTTGTTATGAGAAATGTGGCCGACAAGGACAAAGATTTATTACATGTAGATACCAGGAGAGACTGAGCACAATTGATGAGCTCGATGAATTATTCCCTAGCAGGGGATTCCAATGTGTTTATTCAGAATTTTCTTGAAAGCAAAAAGGAGTATAATAGCATAGGTGTCAGTCGCTTTGAGATCCGCTATCCAGAAAAACAACCAGACAAAAAAAGTAAGAAGTCACTGATAGGTGGCAACCACAGTAAAATTGTTGTGGAACAAAGGAAGAGTGAGTATTTTGAACTGAAGGCGAAACTGCAGAGTTCCCCTGACTACCTACAGGTCCTTGAGGAGCAAACAGCTTTGAACAAGATCTAG

[0057] An open reading frame (ORF) for MOL2 was identified fromnucleotides 1 to 2628. The disclosed MOL2 polypeptide (SEQ ID NO:6)encoded by SEQ ID NO:5 has 876 amino acid residues and is presentedusing the one-letter code in Table 2B. The SignalP, Psort and 5Hydropathy profile of MOL2 indicate that this sequence does have asignal peptide localized between amino acids 57 and 58 (TNA-DS) and islikely to be localized to the plasma membrane (0.4600 certainty).Therefore it is likely that MOL2 is available at the appropriatesub-cellular localization and hence accessible for the therapeutic usesdescribed in this application. TABLE 2B Encoded MOL2 protein sequence.(SEQ ID NO:6)NIYIQVIFQVMTIEKMFSFYFLDYFSLFRSIQLFADCKKMFLWLFLILSALISSTNADSDISVEICNVCSCVSVENVLYVNCEKVSVYRPNQLKPPWSNFYHLNFQNNFLNILYPNTFLNFSHAVSLHLGNNKLQNIEGCAFLGLSALKQLHLNNNELKILRADTFLGIENLEYLQADYNLIKYIERGAFNKLHKLKVLILNDNLISFLPDNIFRFASLTHLDIRGNRIQKLPYIGVLEHIGRVVELQLEDNPWNCSCDLLPLKAWLENMPYNIYIGEAICETPSDLYGRLLKETNKQELCPMGTGSDFDVRILPPSQLENGYTTPNGHTTQTSLHRLVTKPPKTTNPSKISGIVAGKALSNRNLSQIVSYQTRVPPLTPCPAPCFCKTHPSDLGLSVNCQEKNIQSNSELIPKPLNAKKLHVNGNSIKDVDVSDFTDFEGLDLLHLGSNQITVIKGDVFHNLTNLRRLYLNGNQIERLYPEIFSGLHNLQYLYLEYNLIKEISAGTFDSMPNLQLLYLNNNLLKSLPVYIFSGAPLARLNLRNNKFMYLPVSGVLDQLQSLTQIDLEGNPWDCTCDLVALKLWVEKLSDGIVVKELKCETPVQFANIELKSLKNEILCPKLLNKPSAPFTSPAPAITFTTPLGPIRSPPGGPVPLSILILSILVVLILTVFVAFCLLVFVLRRNKKPTVKHEGLGNPDCGSMQLQLRKHDHKTNKKUGLSTEAFIPQTIEQMSKSHTCGLKESETGFMFSDPPGQKVVMRNVADKEKDLLHVDTRKRLSTIDELDELFPSRDSNVFIQNFLESKKEYNSIGVSGFEIRYPEKQPDKKSKKSLIGGNHSKIVVEQRKSEYFELKAKLQSSPDYLQVLEEQTALNKI

[0058] The MOL2 nucleic acid sequence, localized on the q26.3-28 regionof the X chromosome, has 532 of 854 bases (62%) identical to a Homosapiens Insulin-like growth factor binding protein-like protein mRNA(GENBANK-ID:AB020655Iacc:AB020655).

[0059] The full amino acid sequence of the protein of the invention wasfound to have 318 of 672 amino acid residues (47%) identical to, and 445of 672 residues (66%) similar to, the 977 amino acid residueInsulin-like growth factor binding protein-like protein from Homosapiens (SPTREMBL-ACC:094933).

[0060] MOL2 expression in different tissues was examined through TaqManas described below in Example 1.

[0061] Other BLAST results including the sequences used for ClustalWanalysis are presented in Table 2C. TABLE 2C BLAST results for MOL2 GeneIndex/ Protein/ Length Identity Positives Identifier Organism (aa) (%)(%) Expect gi|6691962|emb|CAB6 bG256022.1 853 853/853 853/853 0.05788.1| (AL080239) (similar to (100%) (100%) IGFALS (insulin-like growthfactor binding protein, acid labile subunit)) [Homo sapiens]gi|14424224|sp|O949 HYPOTHETICAL 966 347/699 470/699 1 e−17391|Y918_HUMAN PROTEIN (49%) (66%) KIAA0918 [Homo sapiens]gi|11877257|emb|CAC bG115M3.1 845 372/868 516/868 1 e−172 18888.1|(AL109653) (novel (42%) (58%) protein) [Homo sapiens]gi|12733935|ref|XP_(—) KIAA0848 977 313/675 438/675 e−150 011654.1|protein [Homo (46%) (64%) sapiens] gi|7662336|ref|NP_0 KIAA0848 977313/675 438/675 e−150 55741.1| protein [Homo (46%) (64%) sapiens]

[0062] This information is presented graphically in the multiplesequence alignment given in Table 2D (with MOL2 being shown on line 1)as a ClustalW analysis comparing MOL2 with related protein sequences.

[0063] Table 2E lists the domain description from DOMAIN analysisresults against MOL2. The region from amino acid residue 252 through 302(SEQ ID NO:6) most probably (E=1e−⁶) contains a “leucine rich repeatC-terminal” domain, aligned here in Table 2E. This indicates that theMOL2 sequence has properties similar to those of other proteins known tocontain this domain.

[0064] Chromosomal information

[0065] The Insulin-like growth factor binding protein-like proteindisclosed in this invention maps to chromosome Xq26.3-28.

[0066] Tissue expression

[0067] MOL2 is expressed in at least the following tissues: adrenalgland, lymphatic tissues, and heart. Other tissues known to expressinsulin-like growth factor binding proteins are likely.

[0068] Uses of the Compositions of the Invention

[0069] The expression pattern, map location and protein similarityinformation for MOL2 suggest that this a Insulin-like growth factorbinding protein-like protein may function as a member of theInsulin-like growth factor binding protein-like protein family.Therefore, the MOL2 nucleic acids and proteins are useful in potentialtherapeutic applications implicated, for example but not limited to, invarious pathologies/disorders as described below and/or otherpathologies/disorders. Potential therapeutic uses for MOL2 are, forexample but not limited to, the following: (i) Protein therapeutic, (ii)small molecule drug target, (iii) antibody target (therapeutic,diagnostic, drug targeting/cytotoxic antibody), (iv) diagnostic and/orprognostic marker, (v) gene therapy (gene delivery/gene ablation), (vi)research tools, and (vii) tissue regeneration in vitro and in vivo(regeneration for all these tissues and cell types composing thesetissues and cell types derived from these tissues).

[0070] The MOL2 nucleic acids and proteins are useful in potentialtherapeutic applications implicated in various diseases and disordersdescribed below and/or other pathologies and disorders. For example, butnot limited to, a cDNA encoding the a Insulin-like growth factor bindingprotein-like protein may be useful in gene therapy, and the aInsulin-like growth factor binding protein-like protein may be usefulwhen administered to a subject in need thereof. By way of nonlimitingexample, the compositions of the present invention will have efficacyfor treatment of patients suffering from cancer, diabetes,cardiomyopathy, atherosclerosis, hypertension, congenital heart defects,aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V)canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis,ventricular septal defect (VSD), valve diseases, tuberous sclerosis,scleroderma, obesity, transplantation, hemophilia, hypercoagulation,idiopathic thrombocytopenic purpura, autoimmume disease, allergies,immunodeficiencies, graft versus host disease (GVHD), lymphaedema,adrenoleukodystrophy, and/or congenital adrenal hyperplasia. MOL2, orfragments thereof, may further be useful in diagnostic applications,wherein the presence or amount of the nucleic acid or the protein are tobe assessed.

[0071] These materials are further useful in the generation ofantibodies that bind immuno-specifically to the novel MOL2 substancesfor use in therapeutic or diagnostic methods. These antibodies may begenerated according to methods known in the art, using prediction fromhydrophobicity charts, as described in the “Anti-MOLX Antibodies”section below. The disclosed MOL2 protein has multiple hydrophilicregions, each of which can be used as an immunogen. In one embodiment, acontemplated MOL2 epitope is from about amino acids 75 to 120. Inanother embodiment, a MOL2 epitope is from about amino acids 180 to 200.In additional embodiments, MOL2 epitopes are from about amino acids 280to 380, 400 to 450, 475 to 500, and from about amino acids 680 to 850.These novel proteins can also be used to develop assay systems forfunctional analysis.

[0072] MOL3

[0073] MOL3a

[0074] An additional protein of the invention, referred to herein asMOL3a, is a human Semaphorin B-like protein. The novel nucleic acid of2271 nucleotides (SC85516573_EXT, SEQ ID NO:7) encoding a novelolfactory receptor-like protein is shown in Table 3A. An open readingframe (ORF) was identified beginning with an ATG initiation codon atnucleotides 1-3 and ending with a TAA codon at nucleotides 2269-2271.The nucleotide sequence is presented in Table 3A with the start and stopcodons are in bold letters. TABLE 3A MOL3a Nucleotide SequenceATGGCCCTCCCAGCCCTGGGCCTGGACCCCTGGAGCCTCCTGGGCCTTTTCCTCTTCCAACTGCTTC (SEQID NO:7)AGCTGCTGCTGCCGACGACGACCGCCGGCGGAGGCGGGCAGGGGCCCATGCCCAGCGTCAGATACTATCCAGGGGATGAACGTAGGGCACTTACCTTCTTCCACCAGAAGGGCCTCCAGGATTTTGACACTCTGCTCCTGAGTGGTGATGGAAATACTCTCTACGTGGGGGCTCGAGAAGCCATTCTGGCCTTGGATATCCAGGATCCAGGGGTCCCCAGGCTAAAGAACATGATACCGTGGCCAGCCAGTCACAGAAAAAAGAGTGAATGTGCCTTTAAGAAGAAGAGCAATGAGACACAGTGTTTCAACTTCATCCGTGTCCTGGTTTCTTACAATGTCACCCATCTCTACACCTGCGGCACCTTCGCCTTCAGCCCTCCTTGTACCTTCATTGAACTTCAAGATTCCTACCTGTTGCCCATCTCGGAGGACAAGGTCATGGAGGGAAAAGGCCAAAGCCCCTTTCACCCCGCTCACAACCATACGGCTGTCTTGGTGGATGCGATGCTCTATTCTGGTACTATCAACAACTTCCTGGGCAGTGAGCCCATCCTGATGCGCACACTGGGATCCCAGCCTGTCCTCAAGACCGACAACTTCCTCCGCTGGCTGCATCATGACGCCTCCTTTGTGGCAGCCATCCCTTCGACCCAGGTCGTCTACTTCTTCTTCGAGGAGACAGCCAGCGAGTTTGACTTCTTTGAGAGGCTCCACACATCCCGGGTGGCTAGAGTCTGCAAGAATGACGTGGGCGGCGAAAAGCTGCTGCAGAAGAAGTGGACCACCTTCCTCAAGGCCCAGCTGCTCTGCACCCAGCCGGGGCAGCTGCCCTTCAACGTCATCCGCCACGCGGTCCTGCTCCCCGCCGATTCTCCCACAGCTCCCCACATCTACGCAGTCTTCACCTCCCAGTGGCAGGTTGGCGGGACCAGGAGCTCTGCGGTTTGTGCCTTCTCTCTCTTGGACATTGAACGTGTCTTTAAGGGGAAATACAAAGAGTTGAACAAAGAAACTTCACGCTGGACTACTTATAGGGGCCCTGAGACCAACCCCCGGCCAGGCAGTTGCTCAGTGGGCCCCTCCTCTGATAAGGCCCTGACCTTCATGAAGGACCATTTCCTGATGGATGAGCAAGTGGTGGGGACGCCCCTGCTGGTGAAATCTGGCGTGGAGTATACACGGCTTGCAGTGGAGACAGCCCAGGGCCTTGATGGCCACAGCCATCTTGTCATGTACCTGGGAACCAGTACAGGGTCGCTCCACAAGGCTGTGGTAAGTGGGGACAGCAGTGCTCATCTGGTGGAAGAGATTCAGCTGTTCCCTGACCCTGAACCTGTTCGCAACCTGCAGCTGGCCCCCACCCAGGGTGCAGTGTTTGTAGGCTTCTCAGCAGGTGTCTGGAGGGTGCCCCCAGCCAACTGTAGTGTCTATGAGAGCTGTGTGGACTGTGTCCTTGCCCGGGACCCCCACTGTGCCTGGGACCCTGAGTCCCGACTCTGCTCTCTTAGGAACTCCTGGAAGCAGGACATGGAGCGGGGGAACCCAGAGTGGGCATGTGCCAGTGGCCCCATGAGCAGGAGCCTTCGGCCTCAGAGCCGCCCGCAAATCGTTAAAGAAGTCCTGGCTGTCCCCAACTCCATCCTCGAGCTCCCCTGCCCCCACCTGTCAGCCTTGGCCTCTTATTATTGGAGTCATGGCCCAGCAGCAGTCCCAGAAGCCTCTTCCACTGTCTACAATGGCTCCCTCTTGCTGATAGTGCAGGATGGAGTTGGGGGTCTCTACCAGTGCTGGGCAACTCAGAATGGCTTTTCATACCCTGTGATCTCCTACTGGGTGGACAGCCAGGACCAGACCCTGGCCCTGGATCCTG~CTGGCAGCCATCCCCCGGGAGCATCTGAAGGTCCCGTTGACCAGGGTCAGTCGTGGGGCCGCCCTGGCTCCCCAGCAGTCCTACTGGCCCCACTTTGTCACTGTCACTGTCCTCTTTGCCTTAGTGCTTTCAGGAGCCCTCATCATCCTCGTGGCCTCCCCATTCAGAGCACTCCGGGCTCGGGGCAAGGTTCAGGGCTGTGAGACCCTGCGCCCTGGGGAGAAGGCCCCCTTAAGCAGAGAGCAACACCTCCAGTCTCCCAAGGAATGCAGUACCTCTGCCAGTGATGTGGACGCTGACAACAACTGCCTAGGCACTGAGGTAGCTTAA

[0075] The disclosed MOL3a polypeptide (SEQ ID NO:8) encoded by SEQ IDNO:7 has 756 amino acid residues, and is presented using the one-lettercode in Table 3B. The MOL3a protein was analyzed for signal peptideprediction and cellular localization. SignalP results predict that MOL3ais cleaved between position 31 and 32 (TrA-GG) of SEQ ID NO:8. Psort andHydropathy profiles also predict that MOL3a is likely to be localized atthe plasma membrane (certainty of 0.7300). TABLE 3B Encoded MOL3aprotein sequence. (SEQ ID NO:8)MALPALGLDPWSLLGLFLFQLLQLLLPTTTAGGGGQGPMPRVRYYAGDERRALSFFHQKGLQDFDTLLLSGDGNTLYVGAREAILALDIQDPGVPRLKNMIPWPASDRKKSECAFKKKSNETQCFNFIRVLVSYNVTHLYTCGTFAFSPACTFIELQDSYLLPISEDKVNEGKGQSPFDPAHKHTAVLVDGMLYSGTMNNFLGSEPILMRTLGSOPVLKTDNFLRWLHHDASFVAAIPSTQVVYFFFEETASEFDFFERLHTSRVARVCKNDVGGEKLLQKKWTTFLKAQLLCTQPGQLPFNVIRHAVLLPADSPTAPHIYAVFTSQWQVCGTRSSAVCAFSLLDIERVFKGKYKELNKETSRWTTYRGPETNPRPGSCSVGPSSDKALTFMKDHFLHDEQVVGTPLLVKSGVEYTRLAVETAQGLDGHSHLVNYLGTSTGSLHKAVVSGDSSAHLVEEIQLFPDPEPVPNLQLAPTQGAVFVGFSGGVWRVPRANCSVYESCVDCVLARDPHCAWDPESRLCSLRNSWKQDMERGNPEWACASGPMSRSLRPQSRPQIVKEVLAVPNSILELPCPHLSALASYYWSHGPAAVPEASSTVYNGSLLLIVQDGVGGLYQCWATENGFSYPVISYWVDSQDQTLALDPELAGIPREHVKVPLTRVSGGAALAAQQSYWPHFVTVTVLFALVLSGALIILVASPLRALRARGKVQGCETLRPGEKAPLSREQHLQSPKECRTSASDVDADNNCLGTEVA

[0076] The MOL3a nucleic acid sequence has 1398/1672 (83%) identical toa mouse Semaphorin B mRNA (GENBANK-ID: X85991).

[0077] The full amino acid sequence of MOL3a was found to have 628 of760 (82%) identical to, and 674 of 760 residues (88%) homologous with,the 760 amino acid residue Semaphorin B protein from mouse (ptnr:SWISSNEW-ACC:Q62178).

[0078] MOL3a expression in different tissues was examined through TaqManas described below in Example 1.

[0079] MOL3a also has high homology to the proteins disclosed in theBLASTP searches of the proprietary PATP database shown in Table 3C.TABLE 3C BLAST results for MOL3a Gene Index/ Protein/ Length IdentityPositives Identifier Organism (aa) (%) (%) Expect patp:AAB24084 HumanPR01317 761 751/761 753/761 0.0 protein (98%) (98%) patp:AAY99418 HumanPR01317 761 751/761 753/761 0.0 (UNQ783) (98%) (98%) patp:AAB66043 HumanTANGO 265 761 751/761 753/761 0.0 (98%) (98%) patp:AAB66167 Unidentified761 751/761 753/761 0.0 (98%) (98%) patp:AAB37984 Human secreted 762743/761 745/761 0.0 protein encoded (97%) (97%) by gene 1 clone HTDAA93patp:AAB66045 Human TANGO 265 730 720/730 722/730 0.0 mature protein(98%) (98%) patp:AAB66046 Human TANGO 265 652 642/652 644/652 0.0extracellular (98%) (98%) domain

[0080] Tissue Localization

[0081] MOL3a is expressed in at least the following tissues: PituitaryGland, Thalamus

[0082] Chromosomal Localization

[0083] MOL3a maps to chromosome 1.

[0084] MOL3b

[0085] In the present invention, the target sequence identifiedpreviously, MOL3a, was subjected to the exon linking process to confirmthe sequence. PCR primers were designed by starting at the most upstreamsequence available, for the forward primer, and at the most downstreamsequence available for the reverse primer. In each case, the sequencewas examined, walking inward from the respective termini toward thecoding sequence, until a suitable sequence that is either unique orhighly selective was encountered, or, in the case of the reverse primer,until the stop codon was reached. Such primers were designed based on insilico predictions for the full length cDNA, part (one or more exons) ofthe DNA or protein sequence of the target sequence, or by translatedhomology of the predicted exons to closely related human sequencessequences from other species. These primers were then employed in PCRamplification based on the following pool of human cDNAs: adrenal gland,bone marrow, brain—amygdala, brain—cerebellum, brain—hippocampus,brain—substantia nigra, brain—thalamus, brain—whole, fetal brain, fetalkidney, fetal liver, fetal lung, heart, kidney, lymphoma —Raji, mammarygland, pancreas, pituitary gland, placenta, prostate, salivary gland,skeletal muscle, small intestine, spinal cord, spleen, stomach, testis,thyroid, trachea, uterus. Usually-the resulting amplicons were gelpurified, cloned and sequenced to high redundancy. The resultingsequences from all clones were assembled with themselves, with otherfragments in CuraGen Corporation's database and with public ESTs.Fragments and ESTs were included as components for an assembly when theextent of their identity with another component of the assembly was atleast 95% over 50 bp. In addition, sequence traces were evaluatedmanually and edited for corrections if appropriate. These proceduresprovide the sequence reported below, which is designated MOL3b, oralternatively Accession Number CG53027-02. This is a spliced variant ofthe previously identified sequence (Accession Number SC85516573-EXT) atamino acids 293-329.

[0086] A protein of the invention, referred to herein as MOL3b, is ahuman Semaphorin B-like protein. The novel nucleic acid of 2281nucleotides (CG53027-02, SEQ ID NO:9) encoding a Semaphorin B-likeprotein is shown in Table 3D. An open reading frame (ORF) was identifiedbeginning with a non-initiating codon for the mature protein atnucleotides 2-4 and ending with non-stop codon at nucleotides 2264-2266.The open reading frame may be extendable in both the 5′ and 3′directions because of the lack of traditional start and stop codons. Thenucleotide sequence is presented in Table 3D with the start and stopcodons in bold letters and the 5′ and 3′ untranslated regionsunderlined. TABLE 3D MOL3b Nucleotide Sequence (SEQ ID NO:9)GCCTGTGCCTAGAGTTTAAGCTACCTCAGTGCCTACGCAGTTGTTGTCAGCGTCCACATCACTGGCAGAGGTCCTGCATTCCTTGGGAGACTGGAGGTGTTGCTCTCTGCTTAACGGOGCCTTCTCCCCAGGGCGCAGGGTCTCACAGCCCTGAACCTTGCCCCGAGCCCGGAGTGCTCTCAATGGGGACGCCACGAGGATGATGAGGGCTCCTGAAAGCACTAAGGCAAAGAGGACAGTGACAGTGACAAAGTGGGGCCAGTACGACTGCTGGGCAGCCACGGCGGCCCCACCACTGACCCTGGTCAACGGGACCTTCACATGCTCCCCGCGGATGCCTGCCAGTTCAGGATCCAGGGCCAGGGTCTCGTCCTGGCTGTCCACCCAGTAGGAGATCACAGGGTATGAAAAGCCATTCTCAGTTGCCCAGCACTGGTAGAGACCCCCAACTCCATCCTGCACTATCAGCAAGACGGAGCCATTGTAGACAGTGGAAGAGGCTTCTGGGACTGCTGCTGCGCCATGACTCCAATAATAAGAGGCCAAGGCTGACACGTCGCGGCAGGGGAGCTCCAGGATGGAGTTGGGGACAGCCAGGACTTCTTTAATGATTTGCGGGCGGCTCTGAGGCCGAAGGCTCCTGCTCATGGGGCCACTGGCACATGCCCACTCTGGGTTCCCCCGCTCCATGTCCTGCTTCCAGGAGTTCAGGTTGGGGGCAGACAGGAGGCAACAGGTTCGGGACTCAGGGTCCCAGGCACAGTGGGGGTCCCGGGCAAGGACACAGTCCACACAGCTCTCATAGACACTACAGTTGGCTCGGGGCACCCTCCAGACACCTCCTGAGAAGCCTACAAACACTGCACCCTGGGTGGGGGCCAGCTGCAGGTTGCGAACAGGTTCACGGTCAGGGAACAGCTGAATCTCTTCCACCAGATGAGCACTGCTGTCCCCACTTACCACAGCCTTGTGGAGCGACCCTGTGGTGGTTCCCAGGTACATGACAAGATGGCTGTGCCCATCAAGGCCCTGGGCTGTCTCCACTGCAAGCCGTGTATACTCCACGCCAGATTTCACCAGCAGGGGCGTCCCCACCACTTGCTCATCCATCAGGAAATGGTCCTTCATGAAGGTCAGCGCCTTATCAGAGGAGGGGCCCACTGAGCAACTGCCTGGCCGGGGGTTGGTCTCAGGGCCCCTATAAGTAGTCCAGCGTGAAGTTTCTTTGTTCAACTCTTTGTATTTCCCCTTAAAGACACGTTCAATGTCCAAGAGAGAGAAGGCACAAACCGCAGAGCTCCTGGTCCCGCCAACCTGCCACTGGGAGGTGAAGACTGCGTAGATGTGGGGAGCTGTGGGAGAATCCGCCGGGAGCAGGACCGCGTGGCGGATGACGTTGAAGGGCAGCTGCCCCGGCTGGGTGCAGAGCAGCTGGGCCTTCAGGAAGGTGGTCCACTTCTTCTGCAGCAGCTTTTCGCCGCCCACGTCATTCTTGCAGACTCTAGCCACCCGCGATGTGTGGAGCCTCTCAAAGAAGTCAAACTCGCTGGCTGTCTCCTCGAAGAACAAGTAGACGACCTGGGTCGAAGGGATGGCTGCCACAAAGGAGGCGTCATGATGCAGCCAGCGGAGGAAGTTGTCGGTCTTGAGGACAGGCTGGGATCCCAGTGTGCGCATCAGGATGGGCTCACTGCCCAGGAAGTTGTTCATAGTACCAGAATAGAGCATCCCATCCACCAAGACAGCCGTATGCTTGTGAGCGGGGTCAAAGGGGCTTTGGCCTTTTCCCTCCATGACCTTGTCCTCCGAGATGGGCAACAGGTAGGAATCTTGAAGTTCAATGAAGGTACAAGCAGGGCTGAAGGCGAAGGTGCCGCAGGTGTAGAGATGGGTGACATTGTAAGAAACCAGGACACGGATGAAGTTGAAACACTGTGTCTCATTGCTCTTCTTCTTAAAGGCACATTCACTCTTTTTTCTGTCACTGGCTGGCCACGGTATCATGTTCTTTAGCCTGGGGACCCCTGGATCCTGGATATCCAAGGCCACAATGGCTTCTCGAGCCCCCACGTAGAGAGTATTTCCATCACCACTCAGGAGCAGAGTGTCAAAATCCTGGAGGCCCTTCTGGTGGAAGAAGCTAAGTGCCCTACGTTCATCCCCTGCATAGTATCTGACCCTGCGCATGGGCCCCTGCCCGCCTCCCCCCGCGGTCGTCGTCGGCAGCAGCAGCTCAAGCAGTTGGAAGAGGAAAAGGCCCAGGA GGCTCCAGGGGTCCACG

[0087] The disclosed MOL3b polypeptide (SEQ ID NO: 10) encoded by SEQ IDNO:9 has 754 amino acid residues, and is presented using the one-lettercode in Table 3E. The MOL3b protein was analyzed for signal peptideprediction and cellular localization. SignalP results predict that MOL3bis cleaved between position 24 and 25 (TTA-GG) of SEQ ID NO: 10. Psortand Hydropathy profiles also predict that MOL3b is likely to belocalized at the plasma membrane (certainty of 0.7300). TABLE 3E EncodedMOL3b protein sequence. (SEQ ID NO:10)LDPWSLLGLFLFQLLQLLLPTTTAGGGGQGPMPRVRYYAGDERRALSFFHQKGLQDFDTLLLSGDGNTLYVGAREAILALDIQDPGVPRLKNMIPWPASDRKKSECAFKKKSNETQCFNFIRVLVSYNVTHLYTCGTFAFSPACTFIELQDSYLLPISEDKVMEGKGQSPFDPAHKHTAVLVDGMLYSGTNNNFLGSEPILHRTLGSQPVLKTDNFLRWLHHDASFVAAIPSTQVVYFFFEETASEFDFFERLHTSRVARVCKNUVGGEKLLQKKWTTFLKAQLLCTQPGQLPFNVIRHAVLLPADSPTAPHIYAVFTSQWQVGGTRSSAVCAFSLLDIERVFKGKYKELNKETSRWTTYRGPETNPRPGSCSVGPSSDKALTFMKDHFLMDEQVVGTPLLVKSGVEYTRLAVETAQGLDGHSHLVNYLGTTTGSLHKAVVSGDSSAHLVEEIQLFPDPEPVRNLQLAPTQGAVFVGFSGGVWRVPRANCSVYESCVDCVLARDPHCAWDPESRTCCLLSAPNLNSWKQDMERGNPEWACASGPMSRSLRPQSRPQIIKEVLAVPNSILELPCPHLSALASYYWSHGPAAVPEASSTVYNGSLLLIVQDGVGGLYQCWATENGFSYPVISYWVDSQDQTLALDPELAGIPREHVKVPLTRVSGGAALAAQQSYWPHFVTVTVLFALVLSGALITLVASPLRALRARGKVQGCETLRPGEKAPLSREQHLQSPKECRTSASDVDADNNCLGTEVA

[0088] The MOL3b nucleic acid sequence has 1910 of 2279 bases (83%)identical to a gb:GENBANK-ID:MmRNASEMB lacc:X85991.1 mRNA from Musmusculus (M. musculus mRNA for semaphorin B).

[0089] The full amino acid sequence of the protein of the invention wasfound to have 722 of 755 amino acid residues (95%) identical to, and 723of 755 amino acid residues (95%) similar to, the 762 amino acid residueptnr:TREMBLNEW-ACC:BAB20087 protein from Homo sapiens (Human) (SEMB).

[0090] The presence of identifiable domains in the protein disclosedherein was determined by searches versus domain databases such as Pfam,PROSITE, ProDom, Blocks or Prints and then identified by the Interprodomain accession number. Significant domains are summarized in Table 3F.TABLE 3F Domain search for MOL3b HNMER is freely distributed under theGNU General Public License(GPL). - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -HMM file: pfamHMMs Sequence file:/data4/genetools/kspytek35060Cg53027_01ProteinFasta.txt - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Query: CG53027_01 Scores for sequence family classification (scoreincludes all domains): Model Description Score  E-value  N ------------------- -----  ------- --- Sema Sema domain 618.4 4.2e−182   1Plexin_repeat Plexin repeat  22.0    0.013   1 integrin_B Integrins,beta chain   6.5    0.063   1 Parsed for domains: Model Domain seq-fseq-t hmm-f hmm-t score  E-value -------- ------- ----- ----- ---------- -----  ------- Sema   1/1    57   471 . . .     1   490 [ ] 618.44.2e−182 integrin_B   1/1   495   509 . . .     1    14 [ .   6.5   0.063 Plexin_repeat   1/1   489   555 . . .     1    67 [ ]  22.0   0.013

[0091] Tissue Localization

[0092] MOL3b is expressed in at least the following tissues: thalamusand Pituitary Gland. Expression information was derived from the tissuesources of the sequences that were included in the derivation of thesequence of MOL3b.

[0093] Chromosomal Localization

[0094] MOL3b maps to chromosome 1. This assignment was made usingmapping information associated with genomic clones, public genes andESTs sharing sequence identity with the disclosed sequence and CuraGenCorporation's Electronic Northern bioinformatic tool.

[0095] The disclosed MOL3a protein (SEQ ID NO:8) also has good identitywith a number of other proteins, as shown in Table 3G. TABLE 3G BLASTresults for MOL3a Gene Index/ Protein/ Length Identity PositivesIdentifier Organism (aa) (%) (%) Expect gi|12248382|dbj|B SEMB [Homo 762719/762 722/762 0.0 AB20087.1| sapiens] (94%) (94%) (AB029394)gi|7305469|ref| sema domain, 760 626/760 671/760 0.0 NP_038686.1|immunoglobulin (82%) (87%) domain (Ig), transmembrane domain (TM) andshort cytoplasmic domain, (semaphorin) 4A [Mus musculus]gi|11641291|ref|N hypothetical 328 318/328 320/328 0.0 P_071762.1|protein (96%) (96%) FLJ12287 similar to semaphorins [Homo sapiens]gi|12698035|dbj|B KIAA1745 893 296/760 422/760 e−123 AB21836.1| protein[Homo (38%) (54%) (AB051532) sapiens] gi|8134698|sp|Q62 SEMAPHORIN 4B782 268/684 382/684 e−123 179|SM4B_MOUSE (SEMAPHORIN C) (39%) (55%)(SEMA C)

[0096] This information is presented graphically in the multiplesequence alignment given in Table 3H (with MOL3a being shown on line 1and MOL3b on line 2) as a ClustalW analysis comparing MOL3 with relatedprotein sequences.

[0097] Table 31 lists the domain description from DOMAIN analysisresults against MOL3. The region from amino acid residue 64 through 478(SEQ ID NO:8) most probably (E=1e⁻¹²¹) contains a PSI, domain found inPlexins, Semaphorins and Integrins, aligned here in Table 3I.Semaphorins are involved in growth cone guidance as well as otherdevelopmental processes. Plexins and integrins are involved indevelopmental processes. The MOL1 sequence likely has properties similarto those of other proteins known to contain this domain

[0098] The protein similarity information, expression pattern, cellularlocalization, and map location for the protein and nucleic acid for MOL3suggest that this Semaphorin B-like protein may have importantstructural and/or physiological functions characteristic of theSemaphorin B family. This family is involved in developmental processesincluding growth cone guidance. MOL3 likely plays a similar role inthose developmental processes. Therefore, the MOL3 nucleic acids andproteins are useful in potential diagnostic and therapeutic applicationsand as a research tool. These include serving as a specific or selectivenucleic acid or protein diagnostic and/or prognostic marker, wherein thepresence or amount of the nucleic acid or the protein are to beassessed. These also include potential therapeutic applications such asthe following: (i) a protein therapeutic, (ii) a small molecule drugtarget, (iii) an antibody target (therapeutic, diagnostic, drugtargeting/cytotoxic antibody), (iv) a nucleic acid useful in genetherapy (gene delivery/gene ablation), (v) an agent promoting tissueregeneration in vitro and in vivo, and (vi) a biological defense weapon.

[0099] The MOL3 nucleic acids and proteins have applications in thediagnosis and/or treatment of various diseases and disorders. Forexample, the compositions of the present invention will have efficacyfor the treatment of patients suffering from: neuronal developmental,organizational, mediated and interactive disorders and disease;endocrine dysfunctions, diabetes, obesity, growth and reproductivedisorders, injury repair as well as other diseases, disorders andconditions.

[0100] These materials are further useful in the generation ofantibodies that bind immuno-specifically to the novel MOL3 substancesfor use in therapeutic or diagnostic methods. These antibodies may begenerated according to methods known in the art, using prediction fromhydrophobicity charts, as described in the “Anti-MOLX Antibodies”section below. The disclosed MOL3 protein has multiple hydrophilicregions, each of which can be used as an immunogen. In one embodiment, acontemplated MOL3 epitope is from about amino acids 30 to 100. Inanother embodiment, a MOL3 epitope is from about amino acids 110 to 150.In additional embodiments, MOL3 epitopes are from about amino acids 160to 200, 210 to 230, 250 to 300, 350 to 400, 450 to 475, 500 to 575, 620to 630, and from about amino acids 700 to 750. These novel proteins canalso be used to develop assay systems for functional analysis.

[0101] MOL4

[0102] The disclosed novel semaphorin-like protein, MOL4 (also referredto herein as SC_(—)111750277_A), is encoded by a nucleic acid, 6408nucleotides long (SEQ ID NO: 11). An 15 open reading frame wasidentified beginning with an ATG initiation codon at nucleotides1400-1402 and ending with a TGA codon at nucleotides 5456-5458. Putativeuntranslated regions upstream from the initiation codon and downstreamfrom the termination codon are underlined in Table 4A, and the start andstop codons are in bold letters. TABLE 4A MOL4 Nucleotide Sequence. (SEQID NO:11)CCTGGGACTCTGGGAGAATGGTCCAGAGCTCATTGTCCTTGTTGATAAAATGATAGATTTGGACTCAATATCCCATGCTGCCTCTTCCAACTTGATTTTTACCCCAGACTGGGCTACCAGACTGGTATGCCCACACATGCCCGTTTCCTTTCTTTTCTTCTCTGCATCTCTGCCTTTGTGTCCAGACCGTGTTTTCCCTTTGCAAGTTTCTCTCCATTCTGCACATTATGAGTTTCAGCATTTCTGTTGCCCTAGAAAGTCTATCTTTGAGATCTTGCACTGTTTCTCTTTTTACAGTGTCTCATAAACTCCCTTCTTGGATTCAGAACCACCCTTTCTTTCCCATTATCCTGTCAAACTGCTTCTTGCCATCGTCCAGGGGTAGGACGATGGCAGGCAGGAGGTGCTTCTCTGGGGCTCTTAGTGTCTCAATTCTTCTGCTTTATCTGGGTTTTCCTTTACCCAGAATTTTATTATGTAAAATGCTTCACTCAGACTTTGTTCTAATTATCCAATTTTTGGCATACTCTAGAAAGTCTTTTGATATTTTCCTTCCTCCAACTTATCTATTTTTATTTCATAGTTCTCTTTGGTTATCTCTTAGAATCACACTTTCCTGGTTTTAATTTTTCAAATCCTTTGTCTTTCTCACTCGTTCTTAGGTCACCTTTTTTTACATTTTCAAATATATTTTTTGTTCAGCAGAGGGCTCCCTTCCCATCCCTCTTGCAGCCCGGGCAGCTAGGATTTGAAGCTTGCCCCTTGAATCTTTCTCTCCCGCCTTCTAGCCATCAGAAACACTAGATCACTTAAACTTGTAAACAATTCGGCCTCGCTCCTTGTGATTGCGCTAAACCTTCCGTCCTCAGCTGAGAACGCTCCACCACCTCCCCGGATCGCTCATCTCTTGGCTGCCCTCCCACTGTTCCTGATGTTATTTTACTCCCCGTATCCCCTACTCGTTCTTCACAATTCTGTAGGGTGCGTATTACTAACCCCAGTTTACAGCTGAGGAAACTGAGGCTTGGAGAGGTTCGCTCGGTATCGTACAGTTTGCAAGGTTAACCCTAATCCGGCCAGTTCTGGCTTTCCAGCCCAGCCCAGCAGCCTAGCCTCCCTCTCTGCCGCTGCAGGTTATAACGGCTCTCCCCCGTTTTACACGAGGTCCCTTCCCCTTCAAATCCACAGGCAGGAAGATCGTTCCGAACTGACGGGGCTGGGGAATGTCGGAGTCCCGAGTGGGGTTTGGGGGAGCTTCCTCAGGCCCTGAGTGTTGGGGTGGGCACGCCGCGCCGATGGCCCTCGGGGATGTCACATTCGAGATGGGGTGACCGAGAACGGCAAGGCGGGATGTGGCAAACGGCGGCAAGTGCTCGGAGTCCTAGGTCTTGCCGCCGGAATGCCGGCCGGGGAAGGGGCTTCGGCCCACCCGGCTGGTCACCACACTCGGCAGGCCCCGGGCGGGAGTCGGCCGAGCAGCCGCGGGATGCAGGGCGCCCCCTCGCGCTCCTCCGCGCGCCTCGAGGCTGGCGGGTGCAGCGCCCGCCGCGGCAGGTCTGCTCCAGCCCCCTCCTCTTTTTCGCTCCCGCTCCCCTCCTTCTCTCCCTTTGCTTCCAACTCCTCCCCCACCGCCCCCTCCCTCCTTCTGCTCCCGCGGTCTCCTCCTCCCTGCTCTCTCCGAGCGCCGGGTCGGGAGCTAGTTGGAGCGCGGGGGTTGGTGCCAGAGCCCAGCTCCGCCGAGCCGGGCGGGTCCGCAGCGCATCCAGCGGCTGCTGGGAGCCCGAGCGCAGCGGGCGCGGGCCCGGGTGCGGACTGCACCGGAGCGCTGAGAGCTGGAGGCCGTTCCTGCGCCGCCGCCCCATTCCCAGACCGGCCGCCAGCCCATCTGGTTAGCTCCCGCCGCTCCGCGCCGCCCGGGAGTCGCGAGCCGCGGGGAACCGGGCACCTGCACCCGCCTCTGGGAGTGAGTGGTTCCAGCTGGTGCCTGGCCTGTGTCTCTTGGATGCCCTGTGGCTTCAGTCCGTCTCCTGTTGCCCACCACCTCGTCCCTGGGCCGCCTGATACCCCAGCCCAACAGCTAAGGTGTGGATGGACAGTAGGGGGCTGGCTTCTCTCACTGGTCAGGGGTCTTCTCCCCTGTCTGCCTCCCGGAGCTAGGACTGCAGAGGGGCCTATCATGGTGCTTGCAGGCCCCCTGGCTGTCTCGCTGTTGCTGCCCAGCCTCACACTGCTGGTGTCCCACCTCTCCAGCTCCCAGGATGTCTCCAGTGAGCCCAGCAGTGAGCAGCAGCTGTGCGCCCTTAGCAAGCACCCCACCGTGGCCTTTGAAGACCTGCAGCCGTGGGTCTCTAACTTCACCTACCCTGGAGCCCGGGATTTCTCCCAGCTGGCTTTGGACCCCTCCGGGAACCAGCTCATCGTGGGAGCCAGGAACTACCTCTTCAGACTCAGCCTTGCCAATGTCTGTCTTCTTCACGCCACAGAGTGGGCCTCCAGTGAGGACACGCGCCGCTCCTGCCAAAGCAAAGGGAAGACTGAGGAGCAGTGTCAGAACTACGTGCGAGTCCTGATCGTCGCCGGCCGGAAGGTGTTCATGTGTGGAACCAATGCCTTTTCCCCCATGTGCACCAGCAGACAGGTGGGGAACCTCAGCCGGACTACTGAGAAGATCAATGGTGTGGCCCGCTGCCCCTATGACCCACGCCACAACTCCACAGCTGTCATCTCCTCCCAGGGGGAGCTCTATGCAGCCACGGTCATCGACTTCTCAGGTCGGGACCCTGCCATCTACCGCAGCCTGGGCAGTGGGCCACCCCTTCGCACTGCCCAATATAACTCCAAGTGGCTTAATGAGCCAAACTTCGTGGCAGCCTATGATATTGGGCTGTTTGCATACTTCTTCCTGCCGGAGAACGCAGTCGAGCACGACTGTGGACGCACCGTGTACTCTCGCGTGGCCCGCGTGTGCAAGAATGACGTGGGGGGCCGATTCCTGCTGGAGGACACATGGACCACATTCATGAAGGCCCGGCTCAACTGCTCCCGCCCGGGCGAGGTCCCCTTCTACTATAACGAGCTGCAGAGTGCCTTCCACTTGCCAGAGCACGACCTCATCTATGGAGTTTTCACAACCAACGTAAACAGCATCGCGGCTTCTGCTGTCTGCGCCTTCAACCTCAGTGCTATCTCCCAGGCTTTCAATGGCCCATTTCGCTACCAGGAGAACCCCAGGGCTGCCTGGCTCCCCATAGCCAACCCCATCCCCAATTTCCAGTGTGGCACCCTGCCTGAGACCGGTCCCAACGAGAACCTGACGGAGCGCAGCCTGCACGACGCGCAGCGCCTCTTCCTGATGAGCGAGGCCGTGCACCCGGTGACACCCGAGCCCTGTGTCACCCAGGACAGCGTGCGCTTCTCACACCTCGTGGTGGACCTGGTGCAGGCTAAAGACACGCTCTACCATGTACTCTACATTGGCACCGAGTCGGGCACCATCCTGAAGGCGCTGTCCACGGCGAGCCGCAGCCTCCACGGCTGCTACCTGGAGGAGCTGCACGTGCTGCCCCCCGGGCGCCGCGAGCCCCTGCGCAGCCTGCGCATCCTGCACAGCGCCCGCGCGCTCTTCGTGGGGCTGAGAGACGGCGTCCTGCGGGTCCCACTGGAGAGGTGCGCCGCCTACCGCAGCCAGGGGGCATGCCTGGGGGCCCGGGACCCGTACTGTGGCTGGGACGGGAAGCAGCAACGTTGCAGCACACTCGAGGACAGCTCCAACATGAGCCTCTGGACCCAGAACATCACCGCCTCTCCTGTCCGGAATGTGACACGGGATGGGGGCTTCGGCCCATGGTCACCATGGCAACCATGTGAGCACTTGGATGGGGACAACTCAGGCTCTTGCCTGTGTCGAGCTCGATCCTGTGATTCCCCTCGACCCCGCTGTGGGGGCCTTGACTGCCTGGGGCCACCCATCCACATCGCCAACTGCTCCAGGAATCGGGCGTGGACCCCGTCGTCATCGTCGGCGCTGTGCAGCACGTCCTGTGGCATCGGCTTCCAGGTCCGCCAGCGAAGTTGCAGCAACCCTGCTCCCCGCCACGGGGGCCGCATCTGCGTGGGCAAGAGCCGGGAGGAACGGTTCTGTAATGAGAACACGCCTTGCCCGGTGCCCATCTTCTGGGCTTCCTGGGGCTCCTGGAGCAAGTGCAGCAGCAACTGTCGACGGGGCATGCAGTCGCGGCGTCGGGCCTGCGAGAACGGCAACTCCTGCCTGGGCTGCGGCGTGGAGTTCAAGACGTCCAACCCCGAGGGCTGCCCCGAACTGCGGCGCAACACCCCCTGGACGCCGTCGCTGCCCGTGAACGTGACGCAGGGCGGGGCACGCCAGGAGCAGCGGTTCCCCTTCACCTGCCGCGCGCCCCTTGCAGACCCGCACGGCCTGCAGTTCGGCAGGAGAAGGACCGAGACGAGGACCTGTCCCGCGGACGGCTCCGGCTCCTGCGACACCGACGCCCTGGTGGAGGACCTCCTGCGCAGCGCGAGCACCTCCCCCCACACGGTCAGCGCGGGCTGGGCCGCCTGGGGCCCGTGGTCGTCCTGCTCCCGGGACTGCGAGCTGGGCTTCCGCGTCCGCAAGAGAACGTGCACTAACCCGGAGCCCCGCAACGGGGGCCTGCCCTGCGTGGGCGATGCTGCCGAGTACCAGGACTGCAACCCCCAGGCTTGCCCAGTTCGGGGTGCTTGGTCCTGCTGGACCTCATGGTCTCCATGCTCAGCTTCCTGTGGTGGCGGTCACTATCAACGCACCCGTTCCTGCACCAGCCCCGCACCCTCCCCAGGTGAGGACATCTGTCTCGGGCTGCACACGGAGGAGGCACTATGTGCCACACAGGCCTGCCCAGAAGGCTGGTCGCCCTGGTCTGAGTGGAGTAAGTGCACTGACGACGGAGCCCAGAGCCGAAGCCCGCACTGTGAGGACCTCCTCCCAGCGTCCAGCGCCTGTGCTGGAAACAGCAGCCAGAGCCGCCCCTGCCCCTACAGCGAGATTCCCGTCATCCTGCCAGCCTCCAGCATGGAGGAGGCCACCGGCTGTGCAGGGTTCAATCTCATCCACTTGGTGGCCACGGGCATCTCCTGCTTCTTGGGCTCTGGGCTCCTGACCCTAGCAGTGTACCTGTCTTGCCAGCACTGCCAGCGTCAGTCCCAGGAGTCCACACTGGTCCATCCTGCCACCCCCAACCATTTGCACTACAAGGGCGGAGGCACCCCGAAGAATGAAAAGTACACACCCATGGAATTCAAGACCCTGAACAAGAATAACTTGATCCCTGATGACAGAGCCAACTTCTACCCATTGCAGCAGACCAATGTGTACACGACTACTTACTACCCAAGCCCCCTGAACAAACACAGCTTCCGGCCCGAGGCCTCACCTGGACAACGGTGCTTCCCCAACAGCTGATACCGCCGTCCTGGGGACTTGGGCTTCTTGCCTTCATAAGGCACAGAGCAGATGGAGATGGGACAGTGGAGCCAGTTTGGTTTTCTCCCTCTGCACTAGGCCAAGAACTTGCTGCCTTGCCTGTGGGGGGTCCCATCCGGCTTCAGAGAGCTCTGGCTGGCATTGACCATGGGGGAAAGGGCTGGTTTCAGGCTGACATATGGCCGCACGTCCAGTTCAGCCCACGTCTCTCATCGTTATCTTCCAACCCACTGTCACGCTGACACTATGCTGCCATGCCTGGGCTGTGGACCTACTGGGCATTTGAGGAACTGGAGAATGGAGATGGCAAGAGGGCAGGCTTTTAAGTTTGGGTTGGAGACAACTTCCTGTGGCCCCCACAAGCTGAGTCTGGCCTTCTCCAGCTGGCCCCAAAAAAGGCCTTTGCTACATCCTGATTATCTCTGAAAGTAATCAATCAAGTGGCTCCAGTAGCTCTGGATTTTCTGCCAGGGCTGGGCCATTGTGGTGCTGCCCCAGTATGACATGGGACCAAGGCCAGCGCAGGTTATCCACCTCTGCCTGGAAGTCTATACTCTACCCACGGCATCCCTCTGGTCAGACGCAGTGAGTACTGGGAACTGGAGGCTGACCTGTGCTTAGAAGTCCTTTAATCTGGGCTGGTACAGGCCTCAGCCTTGCCCTCAATGCACGAAAGGTGGCCCAGGAGAGAGGATCAATGCCACAGGAGGCAGAAGTCTGGCCTCTGTGCCTCTATGGAGACTATCTTCCAGTTGCTGCTCAACAGAGTTGTTGGCTGAGACCTGCTTGGGAGTCTCTGCTGGCCCTTCATCTGTTCAGGAACACACACACACACACACTCACACACGCACACACAATCACAATTTGCTACAGCAACAAAAAAGACATTGGGCTGTGGCATTATTAATTAAAGATGATATCCAGTCTCC

[0103] The 1352 amino acid MOL4 polypeptide (SEQ ID NO: 12) encoded bySEQ ID NO:11 is presented using the one-letter amino acid code in Table4B. The Psort profile for MOL4 predicts that this sequence has no signalpeptide and is likely to be localized in the plasma membrane with acertainty of 0.7900. MOL4 has a molecular weight of 145674.1 Daltons.TABLE 4B MOL4 protein sequence (SEQ ID NO:12)MPAGEGASAHRAGHHTRQARGGSRPSSRGMQGAPSRSSARLEAGGCSARRGRSAPAPSSFSLPLPSFSPFACNSSPTAPSLLLLPRSPPPCSLRAPGRELVGARGLVPEPSSAEPGGSAAHPAAAGSPSAAGAGPGGDCTGALRAGGRSCAAAPFPDRPPAHLVSSRRSAPPGSREPRGTGHLHPPLGVSGSSWCLACVSWMPCGFSPSPVAHHLVPGPPDTPAQQLRCGWTVGGWLLSLVRGLLPCLPPGARTAEGPINVLAGPLAVSLLLPSLTLLVSHLSSSQDVSSEPSSEQQLCALSKHPTVAFEDLQPWVSNFTYPGARDFSQLALDPSGNQLIVGARNYLFRLSLANVSLLQATEWASSEDTRRSCQSKGKTEEECQNYVRVLIVAGRKVFMCGTNAFSPMCTSRQVGNLSRTTEKINGVARCPYDPRHNSTAVISSQGELYAATVIDFSGRDPAIYRSLGSGPPLRTAQYNSKWLNEPNFVAAYDIGLFAYFFLRENAVEHDCGRTVYSRVARVCKNDVGGRFLLEDTWTTFMKARLNCSRPGEVPFYYNELQSAFHLPEQDLIYGVFTTNVNSIAASAVCAFNLSAISQAFNGPFRYQENPRAAWLPIANPIPNFQCGTLPETGPNENLTERSLQDAQRLFLMSEAVQPVTPEPCVTQDSVRFSHLVVDLVQAKDTLYHVLYIGTESGTILIALSTASRSLHGCYLEELHVLPPGRREPLRSLRILHSARALFVGLRDGVLRVPLERCAAYRSQGACLGARDPYCGWDGKQQRCSTLEDSSNMSLWTQNITACPVRNVTRDGGFGPWSPWQPCEHLDGDNSGSCLCRARSCDSPRPRCGGLDCLGPAIHIANCSRNGAWTPWSSWALCSTSCGIGFQVRQRSCSNPAPRHGGRICVGKSREERFCNENTPCPVPIFWASWGSWSKCSSNCGGGMQSRRRACENGNSCLGCGVEFKTCNPEGCPEVRRNTPWTPWLPVNVTQGGARQEQRFRFTCRAPLADPHGLQFGRRRTETRTCPADGSGSCDTDALVEDLLRSGSTSPHTVSGGWAAWGPWSSCSRDCELGFRVRKRTCTNPEPRNGGLPCVGDAAEYQDCNPQACPVRGAWSCWTSWSPCSASCGGGHYQRTRSCTSPAPSPGEDICLGLHTEEALCATQACPEGWSPWSEWSKCTDDGAQSRSRHCEELLPGSSACAGNSSQSRPCPYSEIPVILPASSMEEATGCAGFNLIHLVATGISCFLGSGLLTLAVYLSCQHCQRQSQESTLVHPATPNHLHYKGGGTPKNEKYTPNEFKTLNKNNLIPDDRANFYPLQQTNVYTTTYYPSPLNKHSFRPEASPGQRCFPNS

[0104] The disclosed nucleic acid MOMA sequence has 3226 of 3664 bases(88%) identical to a Mus musculus semaphorin mRNA (GENBANK-ID: ACC:X97818).

[0105] The full amino acid sequence of the disclosed MOL4 polypeptidehas 1021 of 1093 amino acid residues (93%) identical to, and 1053 of1093 residues (96%) positive with, the 1093 amino acid residuesemaphorin SB precursor protein from Mus musculus(ptnr:SPTREMBL-ACC:Q60519), and 971 of 973 amino acid residues (99%)identical to, and 972 of 973 residues (99%) positive with patp:AAY94990Human secreted protein vb21_(—)1, having 999 aa. The C-terminal 1202amino acid residues of MOL4 are 100% identical to human KIAA1445 PROTEIN(TREMBLNEW-ACC:BAA95969).

[0106] MOL4 expression in different tissues was examined through TaqManas described below in Example 1.

[0107] A SNP for MOL4 and the corresponding amino acid change it wouldcause is shown in Table 4C. The SNP was identified using the techniquesdisclosed in Example 3. TABLE 4C SNP for MOL4 AA Consensus Base ChangeResidue Position Change Position Change 2046 C > T 682 A > V

[0108] In a search of CuraGen's proprietary human expressed sequenceassembly database, assemblies 111750277 (589 nucleotides) and 87739769(896 nucleotides) were identified as having >95% homology to thispredicted semaphorin sequence (FIG. 3A2). This database is composed ofthe expressed sequences (as derived from isolated mRNA) from more than96 different tissues. The mRNA is converted to cDNA and then sequenced.These expressed DNA sequences are then pooled in a database and thoseexhibiting a defined level of homology are combined into a singleassembly with a common consensus sequence. The consensus sequence isrepresentative of all member components. Since the nucleic acid of thedescribed invention has >95% sequence identity with the CuraGenassembly, the nucleic acid of the invention likely represents anexpressed semaphorin sequence.

[0109] The DNA assembly 111750277 has 3 components and was found byCuraGen to be expressed in the following tissues: Lymph node and Lung.The DNA assembly 87739769 has 7 components and was found by CuraGen tobe expressed in the following tissues: Brain, Uterus, and Lung.

[0110] BLASTP (Non-Redundant Composite database) analysis of the besthits for alignments with MOL4 are listed in Table 4D. TABLE 4D BLASTPresults for MOL4 Gene Index/ Protein/ Length Identity PositivesIdentifier Organism (aa) (%) (%) Expect gi|7305473|ref| sema domain,seven 1093 1021/1093 1053/1093 0.0 NP_038689.1| thrombospondin repeats(93%) (95%) (type 1 and type 1- like), transmembrane domain (TM) andshort cytoplasmic domain, (sem [Mus musculus] gi|7959149|dbj| KIAA1445protein [Homo 1202 1202/1202 1202/1202 0.0 BAA95969.1| sapiens] (100%)(100%) (AB040878) gi|4506881|ref| sema domain, seven 1074  616/1043 781/1043 0.0 NP_003957.1| thrombospondin repeats (59%) (74%) (type 1and type 1- like), transmembrane domain (TM) and short cytoplasmicdomain, (semaphorin) 5A; semaphorin F; sema domain, seven thrombospondinrepeats (type 1 and type 1- like), transmembrane domain (TM)gi|12731706|ref| sema domain, seven 1074  617/1043  781/1043 0.0XP_004042.2| thrombospondin repeats (59%) (74%) (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain,(semaphorin) 5A [Homo sapiens] gi|6677915|ref| sema domain, seven 1077 617/1046  776/1046 0.0 NP_033180.1| thrombospondin repeats (58%) (73%)(type 1 and type 1- like) , transmembrane domain (TM) and shortcytoplasmic domain, (sem; M-Sema D [Mus musculus]

[0111] This information is presented graphically in the multiplesequence alignment given in Table 4E (with MOMA being shown on line 1)as a ClustalW analysis comparing MOL4 with related sequences.

[0112] Tables 4F-4K list the domain descriptions from DOMAIN analysisresults against MOL4.

[0113] The region from amino acid residue 327 through 725 (SEQ ID NO:12) most probably (E=2e⁻¹¹⁸) contains a Sema domain found inSemaphorins, aligned here in Table 4F. Semaphorins are involved ingrowth cone guidance, axonal pathfinding, and other developmentalprocesses. The region from amino acid residue 1057 through 1109 (SEQ IDNO: 12) most probably (E=3e⁻⁹) contains a Thrombospondin type-1 repeatfound in thrombospondin-1 that binds to and activates TGF-beta, alignedhere in Table 4G. TGF-beta is involved in the modulation ofproliferation in many cell types. The region from amino acid residue 868through 921 (SEQ ID NO:12) most probably (E=4e⁻⁸) also contains aThrombospondin type-1 repeat found in thrombospondin-1 that binds to andactivates TGF-beta, aligned here in Table 4H. The region from amino acidresidue 926 through 972 (SEQ ID NO: 12) most probably (E=6e⁻⁷) alsocontains a Thrombospondin type-1 repeat found in thrombospondin-1 thatbinds to and activates TGF-beta, aligned here in Table 4I. The regionfrom amino acid residue 1169 through 1210 (SEQ ID NO:12) most probably(E=0.001) also contains a Thrombospondin type-1 repeat found inthrombospondin-1 that binds to and activates TGF-beta, aligned here inTable 4J. The region from amino acid residue 756 through 803 (SEQ IDNO:12) most probably (E=1e⁻⁵) also contains a Thrombospondin type-1repeat found in thrombospondin-1 that binds to and activates TGF-beta,aligned here in Table 4K. The presence of these domains indicates thatthe MOL4 sequence has properties similar to those of other proteinsknown to contain these domains.

[0114] The above defined information for MOL4 suggests that thissemaphorin-like protein may function as a member of a “Semaphorinfamily”. Therefore, the novel nucleic acids and proteins identified heremay be useful in potential therapeutic applications implicated in (butnot limited to) various pathologies and disorders as indicated below.The potential therapeutic applications for MOT4 include, but are notlimited to: protein therapeutic, small molecule drug target, antibodytarget (therapeutic, diagnostic, drug targeting/cytotoxic antibody),diagnostic and/or prognostic marker, gene therapy (gene delivery/geneablation), research tools, tissue regeneration in vivo and in vitro ofall tissues and cell types composing (but not limited to) those definedhere.

[0115] The MOMA nucleic acids and proteins are useful in potentialtherapeutic applications implicated in Parkinson's disease, psychoticand neurological disorders, Alzheimers disease, cancer including but notlimited to lung or breast cancer, endocrine disorders, inflammatorydisorders, gastro-intestinal disorders and disorders of the respiratorysystem, and/or other pathologies and disorders. For example, a cDNAencoding the semaphorin-like protein may be useful in gene therapy, andthe semaphorin-like protein may be useful when administered to a subjectin need thereof. By way of nonlimiting example, the compositions of thepresent invention will have efficacy for treatment of patients sufferingfrom Parkinson's disease, psychotic and neurological disorders,Alzheimers disease, cancer including but not limited to lung or breastcancer, endocrine disorders, inflammatory disorders, gastro-intestinaldisorders and disorders of the respiratory system. MOL4, or fragmentsthereof, may further be useful in diagnostic applications, wherein thepresence or amount of the nucleic acid or the protein are to beassessed.

[0116] These materials are further useful in the generation ofantibodies that bind immuno-specifically to the novel MOL4 substancesfor use in therapeutic or diagnostic methods. These antibodies may begenerated according to methods known in the art, using prediction fromhydrophobicity charts, as described in the “Anti-MOLX Antibodies”section below. The disclosed MOL4 protein has multiple hydrophilicregions, each of which can be used as an immunogen. In one embodiment, acontemplated MOL4 epitope is from about amino acids 5 to 75. In anotherembodiment, a MOL4 epitope is from about amino acids 100 to 200. Inadditional embodiments, MOL4 epitopes are from about amino acids 300 to375, 420 to 600, 600 to 675, 775 to 850, 900 to 1150,, and from aboutamino acids 1250 to 1350. These novel proteins can also be used todevelop assay systems for functional analysis.

[0117] MOL5

[0118] MOL5a

[0119] The disclosed novel semaphorin 4C-like nucleic acid of 3868nucleotides, MOL5a, (also referred to as SC20422974-A) is shown in Table5A. An ORF begins with an ATG initiation codon at nucleotides 453-455and ends with a TGA codon at nucleotides 2952-2954. A putativeuntranslated region upstream from the initiation codon and downstreamfrom the termination codon is underlined in Table 5A, and the start andstop codons are in bold letters. TABLE 5A MOL5a Nucleotide Sequence (SEQID NO:13)CGACTATCCATGAAGCCCGGAGCCCCAGTGGCTGCAAGGCCTGCTGCCTGAGGTTCTTTCAAGAAACTCAAACCTCTTAGGCCTGAGTGTGTATGTTGGGCGGGGGTCCCCTTTTTATTTCTCAAATGATTTCCTGTTGCGCAGAGGTAGTGGTGGGTCTGGAGGCCAGGGAGGGCTTCCCGGAGCCTGTTTAGCCTTCAGCCAACTCAACTCCTCCCCGCTTCCCAGGGAGACCTGTGGTCTTTTAGGCAGAGGCCAAGTGTGGGGACTTAGGTCCACCTCCAAAGAGAAGGGGAAGGAGGGCACCGGGGCTCCTGGAAGGCCTGATGAGGAGTCCTGTGGCCTCTCCTGCTGCGGGCCCCTCTGGTTTGCTTTCTCTGGCTGTGATTTCTGACCATGTCTTTTCCCTCAGCAGGACAGCTGGCCTGAAGCTCAGAGCCGGGGCGTGCGCCATGGCCCCACACTGGGCTGTCTGGCTGCTGGCAGCAAGGCTGTGGGGCCTGGGCATTGGGGCTGAGGTGTGGTGGAACCTTGTGCCGCGTAAGACAGTGTCTTCTGGGGAGCTGGCCACGGTAGTACGGCGGTTCTCCCAGACCGGCATCCAGGACTTCCTGACACTGACGCTGACGGAGCCCACTGGGCTTCTGTACGTGGGCGCCCGAGAGGCGCTGTTTGCCTTCAGTGTAGAGGCTCTGGAGCTGCAAGGAGCGATCTCCTGGGAGGCCCCCGTGGAGAAGAAGACTGAGTGTATCCAGAAAGGGAAGAACAACCAGACCGAGTGCTTCAACTTCATCCGCTTCCTGCAGCCCTACAATGCCTCCCACCTGTACGTCTGTGGCACCTACGCCTTCCAGCCCAAGTGCACCTACGTCAACATGCTCACCTTCACTTTGGAGCATGGAGAGTTTGAAGATGGGAAGGGCAAGTGTCCCTATGACCCAGCTAAGGGCCATGCTGGCCTTCTTGTGGATGGTGAGCTGTACTCGGCCACACTCAACAACTTCCTGGGCACGGAACCCATTATCCTGCGTAACATGGGGCCCCACCACTCCATGAAGACAGAGTACCTGGCCTTTTGGCTCAACGAACCTCACTTTGTAGGCTCTGCCTATGTACCTGAGAGTGTGGGCAGCTTCACGGGGGACGACGACAAGGTCTACTTCCTCTTCAGGGAGCGGGCAGTGGAGTCCGCCTGCTATGCCGAGCAGGTGGTGGCTCGTGTGGCCCGTGTCTGCAAGGGCGATATGGGGGGCGCACGGACCCTGCAGAGGAAGTGGACCACGTTCCTGAAGGCGCGGCTGGCATGCTCTGAAAAGAACTGGCAGCTCTACTTCAACCAGCTGCAGGCGATGCACACCCTGCAGGACACCTCCTGGCACAACACCACCTTCTTTGGGGTTTTTCAAGCACAGTGGGGTGACATGTACCTGTCGGCCATCTGTGAGTACCAGTTGGAAGAGATCCAGCGGGTGTTTGAGGGCCCCTATAAGGAGTACCATGAGGAAGCCCAGAAGTGGGACCGCTACACTGACCCTGTACCCAGCCCTCGGCCTGGCTCGTGCATTAACAACTGGCATCGGCGCCACGGCTACACCAGCTCCCTGGAGCTACCCGACAACATCCTCAACTTCGTCAAGAAGCACCCGCTGATGGAGGAGCAGGTGGGGCCTCGGTGGAGCCGCCCCCTGCTCGTGAAGAAGGGCACCAACTTCACCCACCTGGTGGCCGACCGGGTTACAGGACTTGATGGAGCCACCTATACAGTGCTGTTCATTGGCACAGGTCAGGCATGGCTGCTCAAGGCTGTGAGCCTGGGGCCCTGGGTTCACCTGATTGAGGAGCTGCAGCTGTTTGACCAGGAGCCCATGAGAAGCCTGGTGCTATCTCAGTCGCAGAAGCTGCTCTTTGCCGGCTCCCGCTCTCAGCTGGTGCAGCTGCCCGTGGCCGACTGCATGAAGTATCGCTCCTGTGCAGACTGTGTCCTCGCCCGGGACCCCTATTGCGCCTGGAGCGTCAACACCAGCCGCTGTGTGGCCGTGGGTGGCCACTCTGGGTCCTTTCTGATCCAGCATGTGATGACCTCGGACACTTCAGGCATCTGCAACCTCCGTGGCAGTAAGAAAGTCAGGCCCACTCCCAAAAACATCACGGTGGTGGCGGGCACAGACCTGGTGCTGCCCTGCCACCTCTCCTCCAACTTGGCCCATGCCCGCTGGACCTTTGGGGGCCGGGACCTGCCTGCGGAACAGCCCGGGTCCTTCCTCTACGATGCCCGGCTCCAGGCCCTGGTTGTGATGGCTGCCCAGCCCCGCCATGCCGGGGCCTACCACTGCTTTTCAGAGGAGCGAGCAGGGGGCGCGGCTGGCTGCTGCTACCTTGTGGCTGTCGTGGCAGGCCCGTCGGTGACCTTGGAGGCCCGGGCCCCCCTGGAAAACCTGGGGCTGGTGTGGCTGGCGGTGGTGGCCCTGGGGGCTGTGTGCCTGGTGCTGCTGCTGCTGGTGCTGTCATTGCGCCGGCGGCTGCGGGAAGAGCTGGAGAAAGGGGCCAAGGCTACTGAGAGGACCTTGGTGTACCCCCTGGAGCTGCCCAAGGAGCCCACCAGTCCCCCCTTCCGGCCCTGTCCTGAACCAGATGAGAAACTTTGGGATCCTGTCGGTTACTACTATTCAGATGGCTCCCTTAAGATAGTACCTGGGCATGCCCGGTGCCAGCCCGGTGGGGGGCCCCCTTCGCCACCTCCAGGCATCCCAGGCCAGCCTCTGCCTTCTCCAACTCGGCTTCACCTGGGGGGTGGGCGGAACTCAAATGCCAATGGTTACGTGCGCTTACAACTAGGAGGGGAGGACCGGGGAGGGCTCGGGCACCCCCTGCCTGAGCTCGCGGACTGACTGAGACGCAAACTGCAGCAACGCCAGCCACTGCCCGACTCCAACCCCGAGGAGTCATCAGTATGAGGGGAACCCCCACCGCGTCGGCGGGAAGCGTGGGAGGTGTAGCTCCTACTTTTGCACAGGCACCAGCTATCTCAGGGACATGGCACGGGCACCTGCTCTGTCTGGGACAGATACTGCCCAGCACCCACCCGGCCATGAGGACCTGCTCTGCTCAGCACGGGCACTGCCACTTGGTGTGGCTCACCAGGGCACCAGCCTCGCAGAAGGCATCTTCCTCCTCTCTGTGAATCACAGACACGCGGGACCCCAGCCGCCAAAACTTTTCAAGGCAGAAGTTTCAAGATGTGTGTTTGTCTGTATTTGCACATGTGTTTGTGTGTGTGTGTATGTGTGTGTGCACGCGCGTGCGCGCTTGTGGCATAGCTTCCTGTTTCTGTCAAGTCTTCCCTTGGCCTGGGTCCTCCTGGTGAGTCATTGGAGCTATGAAGGGGAAGGGGTCGTATCACTTTGTCTCTCCTACCCCCACTGCCCCGAGTGTCGGGCAGCGATGTACATATGGAGGTGGGGTGGACAGGGTGCTGTGCCCCTTCAGAGGGAGTGCAGGGCTTGGGGTGGGCCTAGTCCTGCTCCTAGGGCTGTGAATGTTTTCAGGGTGGGGGGAGGGAGATGGAGCCTCCTGTGTGTTTGGGGGGAAGGGTGGGTGGGGCCTCCCACTTGGCCCCGGGGTTCAGTGGTATTTTATACTTGCCTTCTTCCTGTACAGGGCTGGGAAAGGCTGTGTGAGGGGAGAGAAGGGAGAGGGTGGGCCTGCTGTGGACAATGGCATACTCTCTTCCAGCCCTAGGAGGAGGGCTCCTAACAGTGTAACTTATTGTGTCCCCGCGTATTTATTTGTTGTAAATATTTGAGTATTTTTATATTGACAAATAAAATGGAGAAAAAAAAAAAAAAAAAAAAAAAAGTCGTATCGATGT

[0120] The MOL5a protein encoded by SEQ ID NO:13 has 833 amino acidresidues and is presented using the one-letter code in Table 5B. ThePsort profile for MOL5a predicts that this sequence is likely to belocalized at the mitochondrial inner membrane with a certainty of 0.8000or plasma membrane with a certainty of 0.7000. MOL5a has a cleavage sitebetween amino acods 20 and 21 (GIG-AE), and a molecular weight of92617.0 Daltons. TABLE 5B Encoded MOL5a protein sequence (SEQ ID NO:14)MAPHWAVWLLAARLWGLGIGAEVWWNLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTEPTGLLYVGAREALFAFSVEALELQGAISWEAPVEKKTECIQKGKNNQTECFNFIRFLQPYNASHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSATLNNFLGTEPIILRNNGPHHSHKTEYLAFWLNEPHFVGSAYVPESVGSFTGDDDKVYFLFRERAVESDCYAEQVVARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQLYFNQLQAMHTLQDTSWHNTTFFGVFQAQWGDMYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTDPVPSPRPGSCINNWHRRHGYTSSLELPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNFTHLVADRVTGLDGATYTVLFIGTGQAWLLKAVSLGPWVHLIEELQLFDQEPMRSLVLSQSQKLLFAGSRSQLVQLPVADCMKYRSCADCVLARDPYCAWSVNTSRCVAVGGHSGSFLIQHVMTSDTSGICULRGSKKVRPTPKNITVVAGTDLVLPCHLSSNLAHARWTFGGRDLPAEQPGSFLYDARLQALVVMAAQPRHAGAYHCFSEEQGARLAAEGYLVAVVAGPSVTLEARAPLENLGLVWLAVVALGAVCLVLLLLVLSLRRRLREELEKGAKATERTLVYPLELPKEPTSPPFRPCPEPDEKLWDPVGYYYSDGSLKIVPGHARCQPGGGPPSPPPGIPGQPLPSPTRLHLGGGRNSNANGYVRLQLGGEDRGGLGHPLPELADELRRKLQQRQPLPDSNPEESSV

[0121] The disclosed nucleic acid sequence for MOL5a has 2917 of 3443bases (84%) identical to a semaphorin 4C mRNA (GENBANK-ID:S79463|acc:S79463) (E=0.0).

[0122] The full MOL5a amino acid sequence has 729 of 834 amino acidresidues (87%) identical to, and 772 of 834 residues (92%) positiveswith, the 834 amino acid semaphorin 4C Precursor protein from Musmusculus (Mouse) (ptnr:SPTREMBL-ACC: Q64151) (E=0.0). In addition, thisprotein contains the following protein domains (as defined by Interpro)at the indicated nucleotide positions: Sema domain (a.a. 53-481;IPR001627), integrin-B (a.a. 505-519; IPR000413), Plexin_repeat (a.a.499-551; IPR002165), ig (a.a. 570-629; IPR000353)

[0123] MOL5a expression in different tissues was examined through TaqManas described below in Example 1.

[0124] Chromosomal Localization

[0125] MOL5a has been localized to human chromosome 2.

[0126] MOL5b

[0127] Another disclosed novel semaphorin 4C-like nucleic acid of 2558nucleotides, MOL5b, (also referred to as SC14998905_EXT) is shown inTable 5C. An ORF begins with an ATG initiation codon at nucleotides21-23 and ends with a TGA codon at nucleotides 2520-2522. A putativeuntranslated region upstream from the initiation codon and downstreamfrom the termination codon is underlined in Table 5C, and the start andstop codons are in bold letters. TABLE 5C MOL5b Nucleotide Sequence (SEQID NO:15) TCAGAGCCGGGGCGTGCGCCATGGCCCCACACTGGCTGTCTGGCTGCTGGCAGCAAGGCTGTGGGGCCTGGGCATTGGGGCTGAGGTGTGGTGGAACCTTGTGCCGCGTAAGACAGTGTCTTCTGGGGAGCTGGCCACGGTAGTACGGCGGTTCTCCCAGACCGGCATCCAGGACTTCCTGACACTGACGCTGACGGAGCCCACTGGGCTTCTGTACGTGGGCGCCAGGGACCATGCCTCTGCACTGGGCGTCCCTGTGTTGCTGCTGCAGGCTGTGATCTCCTGGGAGGCCCCCGTGGAGAAGAAGACTGAGTGTATCCAGAAAGGGAAGAACAACCAGACCGAGTGCTTCAACTTCATCCGCTTCCTGCAGCCCTACAATGCCTCCCACCTGTACGTCTGTGGCACCTACGCCTTCCAGCCCAAGTGCACCTACGTCAACATGCTCACCTTCACTTTGGAGCATGGAGAGTTTGAAGATCGGAACGGCAAGTGTCCCTATGACCCAGCTAAGGGCCATGCTGGCCTTCTTGTGGATGGTGAGCTGTACTCGGCCACACTCAACAACTTCCTGGGCACGGAACCCATTATCCTGCGTAACATGGGGCCCCACCACTCCATGAAGACAGAGTACCTGCCCTTTTGGCTCAACGAACCTCACTTTGTAGGCTCTGCCTATGTACCTGAGAGTGTGGGCAGCTTCACGGGGGACGACGACAAGGTCTACTTCTTCTTCAGGGAGCGGGCAGTGGAGTCCGACTGCTATGCCGAGCAGGTGGTGGCTCGTGTGGCCCGTGTCTGCAAGGGCGATATGGGGGGCGCACGGACCCTGCAGACGAAGTCGACCACGTTCCTGAACGCGCGGCTGGCATGCTCTGCCCCGAACTCGCAGCTCTACTTCAACCAGCTGCAGGCGATGCACACCCTGCAGGACACCTCCTGGCACAACACCACCTTCTTTGGGGTTTTTCAAGCACAGTGGGGTGACATGTACCTGTCGGCCATCTGTGAGTACCAGTTGGAAGAGATCCAGCGGGTGTTTGAGGGCCCCTATAAGGAGTACCATGAGGAAGCCCAGAAGTGGGACCGCTACACTGACCCTGTACCCAGCCCTCGGCCTGGCTCCTGCATTAACAACTGGCATCGGCGCCACGGCTACACCAGCTCCCTGGAGCTACCCGACCCATCCCTCAACTTCGTCAAGAAGCACCCGCTGATGGAGGAGCAGGTGGGGCCTCGGTGGAGCCGCCCCCTGCTCGTGAAGAAGGGCACAGACTTCACCCACCTGGTGGCCGACCGGGTTACAGGACTTGATGGAGCCACCTATACAGTGCTGTTCATTGGCACAGGAGACGGCTGGCTGCTCAAGGCTGTGACCCTGGGGCCCTGGGTTCACCTGATTGAGGAGCTGCAGCTGTTTGACCAGGAGCCCATGAGAAGCCTGGTGCTATCTCAGAGCAAGAAGCTGCTCTTTGCCGGCTCCCGCTCTCAGCTGGTGCACCTGCCCGTGGCCGACTGCATCAAGTATCGCTCCTGTGCAGACTGTGTCCTCGCCCGGGACCCCTATTGCGCCTGGAGCGTCAACACCAGCCGCTGTGTGGCCGTCGGTGGCCACTCTGGATCTCTACTGATCCAGCATGTGATGACCTCGGACACTTCAGGCATCTGCAACCTCCGTGGCAGTAAGAAAGTCAGGCCCACTCCCAAAAACATCACGGTGGTGGCGGGCACAGACCTGGTGCTGCCCTGCCACCTCTCCTCCAACTTGGCCCATGCCCGCTGGACCTTTGGGGGCCGGGACCTGCCTGCCGAACAGCCCGGGTCCTTCCTCTACGATGCCCGGCTCCAGGCCCTGGTTGTGATGGCTGCCCAGCCCCGCCATGCCGGGGCCTACCACTGCTTTTCAGAGGAGCAGGGGGCGCGGCTGGCTGCTGAAGGCTACCTTGTGGCTGTCGTGGCAGGCCCGTCGGTGACCTTGGAGGCCCGGGCCCCCCTGGAAAACCTGGGGCTGGTGTGGCTGGCGGTGGTGGCCCTGGGCGCTGTGTGCCTGGTGCTGCTGCTGCTGGTOCTGTCATTGCGCCGGCGGCTGCGGGAAGAGCTGGAGAAAGGGGCCAAGGCTACTCAGAGGACCTTGGTGTACCCCCTGGAGCTGCCCAAGGAGCCCACCAGTCCCCCCTTCCGGCCCTGTCCTGAACCAGATGAGAAACTTTGGGATCCTGTCCGTTACTACTATTCAGATGGCTCCCTTAAGATAGTACCTGGGCATGCCCGGTGCCAGCCCGGTGCGGGGCCCCCTTCGCCACCTCCACGCATCCCAGGCCAGCCTCTGCCTTCTCCAACTCGGCTTCACCTGGGGGGTGGGCGGAACTCAAATGCCAATGGTTACGTGCGCTTACAACTAGGAGGGGAGGACCGGGGAGGGCTCGGGCACCCCCTGCCTGAGCTCGCGGATGAACTGAGACGCAAACTGCAGCACGCCAGCCACTGCCCGACTCCAACCCCGAGGAGTCATCAGTATGAGGGGAACCCCCACCGCGTCGGCGGGAAG CGTGGGAG

[0128] The MOL5b protein encoded by SEQ ID NO: 16 has 833 amino acidresidues and is presented using the one-letter code in Table 5D. ThePsort profile for MOL5b predicts that this sequence is likely to belocalized at the plasma membrane with a certainty of 0.7000. TABLE 5DEncoded MOL5b protein sequence (SEQ ID NO:16)MAPHWAVWLLAARLWGLGIGAEVWWNLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTEPTGLLYVGARDHASALGVPVLLLQAVISWEAPVEKKTECIQKGKNNQTECFNFIRFLQPYNASHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSATLNNFLGTEPIILRNMGPHHSMKTEYLAFWLNEPHFVGSAYVPESVGSFTGDDDKVYFFFRERAVESDCYAEQVVARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQLYFNQLQAMHTLQDTSWHNTTFFGVFQAQWGDMYLSATCEYQLEEIQRVFEGPYKEYHEEAQKWDRYTDPVPSPRPGSCINNWHRRHGYTSSLELPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNFTHLVADRVTGLDGATYTVLFIGTGDGWLLKAVSLGPWVHLIEELQLFDQEPMRSLVLSQSKKLLFAGSRSQLVQLPVADCMKYRSCADCVLARDPYCAWSVNTSRCVAVGGHSGSLLIQHVMTSDTSGICNLRGSKKVRPTPKNITVVAGTDLVLPCHLSSNLAHARWTFGGRDLPAEQPGSFLYDARLQALVVMAAQPRHAGAYHCFSEEQGARLAAEGYLVAVVAGPSVTLEARAPLENLGLVWLAVVALGAVCLVLLLLVLSLRRRLREELEKGAKATERTLVYPLELPKEPTSPPFRPCPEPDEKLWDPVGYYYSDGSLKIVPGHARCQPGGGPPSPPPGIPGQPLPSFTRLHLGGGRNSNANGYVRLQLGGEDRGGLGHPLPELADELRRKLQQRQPLPDSNPEESSV

[0129] The disclosed nucleic acid sequence for MOL5b has 1695 of 2019bases (83%) identical to a mouse Semaphorin4C mRNA (GENBANK-ID: S79463)(E=0.0).

[0130] The full MOL5b amino acid sequence has 722 of 834 amino acidresidues (86%) 10 identical to, and 765 of 834 residues (91%) positivewith the amino acid Semaphorin4C HOMOLOG protein from Mouse(S79463_SEMA_(—)4C_MOUSE) (E=0.0). The global sequence homology (asdefined by FASTA alignment with the full length sequence of thisprotein) is 91% amino acid homology and 86% amino acid identity.

[0131] Chromosomal Localization

[0132] MOL5b has been localized to human chromosome 2.

[0133] MOL5c

[0134] In the present invention, the target sequence identifiedpreviously, MOL5b, was subjected to the exon linking process to confirmthe sequence. PCR primers were designed by starting at the most upstreamsequence available, for the forward primer, and at the most downstreamsequence available for the reverse primer. In each case, the sequencewas examined, walking inward from the respective termini toward thecoding sequence, until a suitable sequence that is either unique orhighly selective was encountered, or, in the case of the reverse primer,until the stop codon was reached. Such primers were designed based on insilico predictions for the full length cDNA, part (one or more exons) ofthe DNA or protein sequence of the target sequence, or by translatedhomology of the predicted exons to closely related human sequencessequences from other species. These primers were then employed in PCRamplification based on the following pool of human cDNAs: adrenal gland,bone marrow, brain—amygdala, brain—cerebellum, brain—hippocampus,brain—substantia nigra, brain—thalamus, brain—whole, fetal brain, fetalkidney, fetal liver, fetal lung, heart, kidney, lymphoma—Raji, mammarygland, pancreas, pituitary gland, placenta, prostate, salivary gland,skeletal muscle, small intestine, spinal cord, spleen, stomach, testis,thyroid, trachea, uterus. Usually the resulting amplicons were gelpurified, cloned and sequenced to high redundancy. The resultingsequences from all clones were assembled with themselves, with otherfragments in CuraGen Corporation's database and with public ESTs.Fragments and ESTs were included as components for an assembly when theextent of their identity with another component of the assembly was atleast 95% over 50 bp. In addition, sequence traces were evaluatedmanually and edited for corrections if appropriate. These proceduresprovide the sequence reported below, which is designated MOL5c(Accession Number CG50907-02). This differs from the previouslyidentified sequence, MOL5b, in having 17 different amino acids.

[0135] The disclosed novel semaphorin 4C-like nucleic acid of 3112nucleotides, MOL5c, (also referred to as CG50907-02) is shown in Table5E. An ORF begins with an ATG initiation codon at nucleotides 104-106and ends with a TGA codon at nucleotides 2603-2605. A putativeuntranslated region upstream from the initiation codon and downstreamfrom the termination codon is underlined in Table SE, and the start andstop codons are in bold letters. TABLE 5E MOL5c Nucleotide Sequence (SEQID NO:17)TGCTGCGGGCCCCTCTGGTTTGCTTTCTCTGGCTGTGATTTCTGACCATGTCTTTTCCCTCAGCAGGACAGCTGGCCTGAAGCTCAGAGCCGGGCGTGCGCCATGGCCCCACACTGGGCTGTCTGGCTGCTGGCAGCAAGGCTGTGGGGCCTGGGCATTGGGGCTGAGGTGTGGTGGAACCTTGTGCCGCGTAAGACAGTGTCTTCTGGGGAGCTGGCCACGGTAGTACGGCGGTTCTCCCAGACCGCCATCCAGGACTTCCTGACACTGACGCTGACGGAGCCCACTGGGCTTCTGTACGTGGGCGCCAGGGACCATGCCTCTGCACTGGGCGTCCCTGTGTTFCTGCTGCAGGCTGTGATCTCCTGGGAGGCCCCCGTGGAGAAGAAGACTGAGTGTATCCAGAAAGGGAAGAACAACCAGACCGAGTGCTTCAACTTCATCCGCTTCCTGCAGCCCTACAATGCCTCCCACCTGTACGTCTGTGGCACCTACGCCTTCCAGCCCAAGTGCACCTACGTCAACATGCTCACCTTCACTTTGGAGCATGGAGAGTTTGAAGATGGGAAGGGCAAGTGTCCCTATGACCCAGCTAAGGGCCATGCTGGCCTTCTTGTGGATGGTGAGCTGTACTCGGCCACACTCAACAACTTCCTGGGCACGGAACCCATTATCCTGCGTAACATGGGGCCCCACCACTCCATGAAGACAGAGTACCTGGCCTTTTGGCTCAACGAACCTCACTTTGTAGGCTCTGCCTATGTACCTGAGAGTGTGGGCAGCTTCACGGGGGACGACGACAAGGTCTACTTCTTCTTCAGGGAGCGGGCAGTGGAGTCCGACTGCTATGCCGAGCAGGTGGTGGCTCGTGTGGCCCGTGTCTGCAAGGGCGATATGGGGGGCGCACGGACCCTGCAGAGGAAGTGGACCACGTTCCTGAAGGCGCGGCTGGCATGCTCTGCCCCGAACTGGCAGCTCTACTTCAACCAGCTGCAGGCGATGCACACCCTGCAGGACACCTCCTGGCACAACACCACCTTCTTTGGGGTTTTTCAAGCACAGTGGGGTGACATGTACCTGTCGGCCATCTGTGAGTACCAGTTGGAAGAGATCCAGCGGGTGTTTGAGGGCCCCTATAAGGAGTAGCATGAGGAAGCCCAGAAGTGGGACCGCTACACTGACCCTGTACCCAGCCCTCGGCCTGGCTCGTGCATTAACAACTGGCATCGGCGCCACGGCTACACCAGCTCCCTGGAGCTACCCGACAACATCCTCAACTTCGTCAAGAAGCACCCGCTGATGGAGGAGCAGGTGGGGCCTCGGTGAGCCGCCCCCTGCTCGGTGAAGAAGGGCACCAACTTCACCCACCTGGTGGCCGACCGGGTTACAGGACTTGATGGAGCCACCTATACAGTGCTGTTCATTGGCACAGGAGACGGCTGGCTGCTCAAGGCTGTGAGCCTGGGGCCCTGGGTTCACCTGATTGAGGAGCTGCAGCTGTTTGACCAGGAGCCCATGAGAAGCCTGGTGCTATCTCAGAGCAAGAAGCTGCTCTTTGCCGGCTCCCGCTCTCAGCTGGTGCAGCTGCCCGTGGCCGACTGCATGAAGTATCGCTCCTGTGCAGACTGTGTCCTCGCCCGGGACCCCTATTGCGCCTGGAGCGTCAACACCAGCCGCTGTGTGGCCGTGGGTGGCCACTCTCGATCTCTACTGATCCACCCCATGATGACCTCGGACACTTCAGGCATCTGCAACCTCCGTCGCAGTAAGAAAGTCAGGCCCACTCCCAAAAACATCACGGTGGTGGCGGGCACAGACCTGGTGCTGCCCTGCCACCTCTCCTCCAACTTGGCCCATGCCCGCTGGACCTTTGGGGGCCGGGACCTGCCTGCGGAACAGCCCGGGTCCTTCCTCTACGATGCCCGGCTCCAGGCCCTGGTTGTGATGGCTGCCCAGCCCCGCCATGCCGGGGCCTACCACTGCTTTTCAGAGGAGCAGGGGGCGCGGCTGGCTGCTGAAGGCTACCTTGTGGCTGTCGTGGCAGGCCCGTCGGTGACCTTGGAGGCCCGGGCCCCCCTGGAAAACCTGGGGCTGGTGTGGCTGGCGGTGGTGGCCCTGGGGGCTGTGTGCCTGGTGCTGCTGCTGCTGGTGCTGTCATTGCGCCGGCGGCTGCGGGAAGAGCTGGAGAAACGGGCCAAGGCTACTGAGAGGACCTTGGTGTACCCCCTGGAGCTGCCCAAGGAGCCCACCAGTCCCCCCTTCCGGCCCTGTCCTGAACCAGATGAGAAACTTTGGGATCCTGTCGGTTACTACTATTCAGATGGCTCCCTTAGATAGTACCTGGGCATGCCCGGTGCCAGCCCGGTGGGGCGCCCCCTTCGCCACCTCCAGCCATCCCAGGCCAGCCTCTGCCTTCTCCAACTCGGCTTCACCTGGGGGGTGGGCGGAACTCAAATGCCAATGGTTACGTGCGCTTACAACTAGGAGGGGAGGACCGGGGAGGGCTCGGGCACCCCCTGCCTGAGCTCGCGGATGAACTGAGACGCAAACTGCAGCAACGCCAGCCACTGCCCGACTCCAACCCCGAGGAGTCATCAGTATGAGGGGAACCCCCACCGCGTCGGCGGGAAGGGTGGGAGGTGTAGCTCCTACTTTTGCACAGGCACCAGCTACCTCAGGGACATGGCACGGGCACCTGCTCTGTCTGGGACAGATACTGCCCAGCACCCACCCGGCCATGAGGACCTGCTCTGCTCAGCACGGGCACTGCCACTTGGTGTGGCTCACCAGGGCACCAGCCTCGCAGAAGGCATCTTCCTCCTCTCTGTGAATCACAGACACGCGGGACCCCAGCCCCCAAAACTTTTCAAGGCAGAAGTTTCAAGATGTGTGTTTGTCTGTATTTGCACATGTGTTTGTGTGTGTGTGTATGTGTGTGTGCACGCGCGTGCGCGCTTGTGGCATAGCCTTCCTGTTTCTGTCAAGTCTTCCCTTGGCCTGGGTCCTCCTGGTGAGTCATTGGAGCTATGAAGGGGAAGGGGTCGTATCACTTTGTCTCTCCTACCCCCACTGCCCCGAGTGTCGGGCAGCGATGTACATATGGAGGTGGG

[0136] The MOL5c protein encoded by SEQ ID NO: 17 has 833 amino acidresidues and is presented using the one-letter code in Table 5F. ThePsort profile for MOL5c predicts that this sequence has a signal peptideand the signal peptide is predicted by SignalP to be cleaved betweenamino acid 20 and 21: GIG-AE. This sequence is likely to be localized atthe mitochondrial inner membrane with a certainty of 0.8000 and theplasma membrane with a certainty of 0.7000. TABLE 5F Encoded MOL5cprotein sequence (SEQ ID NO:18)MAPHWAVWLLAARLWGLGIGAEVWWNLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTEPTGLLYVGARDHASALGVPVLLLQAVISWEAPVEKKTECIQKGKNNQTECFNFIRFLQPYNASHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSATLNNFLGTEPIILRNNGPHHSMKTEYLAFWLNEPHFVGSAYVPESVGSFTGDDDKVYFFFRERAVESDCYAEQVVARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQLYFNQLQAMHTLQDTSWHNTTFFGVFQAQWGDNYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTDPVPSPRPGSCINNWHRRHGYTSSLELPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNFTHLVADRVTGLDGATYTVLFIGTGDGWLLKAVSLGPWVHLIEELQLFDQEPNRSLVLSQSKKLLFAGSRSQLVQLPVADCMKYRSCADCVLARDPYCAWSVNTSRCVAVGGHSCSLLIQHVMTSDTSGICNLRGSKKVRPTPKNITVVAGTDLVLPCHLSSNLAHARWTFGGRDLPAEQPGSFLYDARLQALVVMAAQPRHAGAYHCFSEEQGARLAAEGYLVAVVAGPSVTLEARAPLENLGLVWLAVVALGAVCLVLLLLVLSLRRRLREELEKGAKATERTLVYPLELPKEPTSPPFRPCPEPDEKLWDPVGYYYSDGSLKIVPGHARCQPGGGPPSPPPGIPGQPLPSPTRLHLGGGRNSNANGYVRLQLGGEDRCGLGHPLPELADELRRKLQQRQPLPDSNPEESSV

[0137] The disclosed nucleic acid sequence for MOL5c has 2879 of 2906bases (99%) identical to a gb:GENBANK-ID:ABO51526jacc:AB051526.1 mRNAfrom Homo sapiens (Homo sapiens mRNA for KIAA1739 protein, partial cds)(E=0.0).

[0138] The full MOL5 amino acid sequence has 722 of 834 amino acidresidues (86%) identical to, and 765 of 834 amino acid residues (91%)similar to, the 834 amino acid residue ptnr:SWISSPROT-ACC:Q64151 proteinfrom Mus musculus (Mouse) (SEMAPHORIN 4C PRECURSOR (SEMAPHORIN I) (SEMAI) (SEMAPHORIN C-LIKE 1) (M-SEMA F)) (E=0.0). The global sequencehomology (as defined by FASTA alignment with the full length sequence ofthis protein) is 91% amino acid homology and 86% amino acid identity.

[0139] The presence of identifiable domains in the protein disclosedherein was determined by searches versus domain databases such as Pfam,PROSITE, ProDom, Blocks or Prints and then identified by the Interprodomain accession number. Significant domains are summarized in Table 5G.TABLE 5G Domain similarities for MOL5c Scores for sequence familyclassification (score includes all domains): Model Description ScoreE-value N  -------- ----------- ----- ------- --- Sema Sema domain 664.45.8e−196 1 Plexin_repeat Plexin repeat 25.8 0.001 1 ig Immunoglobulindomain 8.5 0.44 1 integrin_B Integrins, beta chain 7.0 0.04 1 Parsed fordomains: Model Domain seq-f seq-t hmm-f hmm-t score  E-value --------------- ----- ----- ----- ----- -----  ------- Sema   1/1    53   481 ..    1   490 [ ] 664.4 5.8e−196 integrin_B   1/1   505   519 ..     1  14[ .   7.0     0.04 Plexin_repeat   1/1   499   551 ..     1   67 [ ] 25.8    0.001 ig   1/1   570   629 ..     1   45 [ ]   8.5     0.44

[0140] The Sema domain occurs in semaphorins, which are a large familyof secreted and transmembrane proteins, some of which function asrepellent signals during axon guidance. Sema domains also occur in ahepatocyte growth factor receptor, in SEX protein (Goodman et al., 1998,Cell 95: 903-916) and in viral proteins.

[0141] The presence of these domains indicates that MOL5c likely hasproperties similar to those of other proteins known to containthis/these domain(s) and similar to the properties of these domains.

[0142] Chromosomal Localization

[0143] MOL5c maps to chromosome 2. This assignment was made usingmapping information associated with genomic clones, public genes andESTs sharing sequence identity with the disclosed sequence and CuraGenCorporation's Electronic Northern bioinformatic tool.

[0144] Tissue Expression

[0145] MOL5c is expressed in at least the following tissues: adrenalgland, bone marrow, brain—amygdala, brain—cerebellum, brain—hippocampus,brain—substantia nigra, brain—thalamus, brain—whole, fetal brain, fetalkidney, fetal liver, fetal lung, heart, kidney, lymphoma—Raji, mammarygland, pancreas, pituitary gland, placenta, prostate, salivary gland,skeletal muscle, small intestine, spinal cord, spleen, stomach, testis,thyroid, trachea and uterus. Expression information was derived from thetissue sources of the sequences that were included in the derivation ofthe sequence of MOL5c.

[0146] MOL5a also has homology to other proteins as shown in BLASTalignment results in Table 5H. TABLE 5H BLAST results for MOL5a GeneIndex/ Protein/ Length Identity Positives Identifier Organism (aa) (%)(%) Expect gi|12698023|dbj|BAB KIAA1739 protein 963 785/801 789/801 0.021830.1| (AB051526) [Homo sapiens] (98%) (98%) gi|8134699|sp|Q6415SEMAPHORIN 4C 834 722/834 765/834 0.0 1|SM4C_MOUSE PRECURSOR (86%) (91%)(SEMAPHORIN I) (SEMA I) (SEMAPHORIN C- LIKE 1) (M-SEMA F)gi|13637386|ref|XP_ hypothetical 510 510/510 510/510 0.0 002614.2|protein FLJ20369 (100%) (100%) [Homo sapiens] qi|8923346|ref|NP_0 semadomain, 510 509/510 509/510 0.0 60259.1| immunoglobulin (99%) (99%)domain (Ig), transmembrane domain TM; cytokeratin 14; adipocyte-derivedleucine aminopeptidase; hypothetical protein MGC10851; hypotheticalprotein FLJ14662; sphingomyelin phosphodiesterase-1, acid lysosomal;Pro- platelet ba> gi|13633937|sp|Q9NT SEMAPHORIN 4G 838 292/673 381/673e−138 N9|SM4G_HUMAN PRECURSOR (43%) (56%)

[0147] This information is presented graphically in the multiplesequence alignment given in Table 51 (with MOL5a being shown on line 1,and MOL5b on line 2) as a ClustalW analysis comparing MOL5 with relatedprotein sequences.

[0148] MOL5b and MOL5c share close homology to each other and thereforeto other proteins as is shown in the BLAST alignment in Table 5J.

[0149] As used herein, any reference to MOL5 encompasses MOL5a, MOL5b,and MOL5c, unless otherwise indicated.

[0150] Table 5K and 5L list the domain descriptions from DOMAIN analysisresults against MOL5. The region from amino acid residue 66 through 487(SEQ ID NO: 14) most probably (E=3e⁻¹²⁵) contains a Sema domain found inSemaphorins, described above under MOL4, and aligned here in Table 5K.The region from amino acid residue 562 through 627 (SEQ ID NO: 14) mostprobably (E=1e⁻⁴) also contains a Sema domain found in Semaphorins,aligned here in Table 5L. This indicates that the MOL5 sequence hasproperties similar to those of other proteins known to contain thisdomain.

[0151] The protein similarity information, expression pattern, cellularlocalization, and map location for MOL5 suggest that this Semaphorin4C-like protein may have important structural and/or physiologicalfunctions characteristic of the Semaphorin family. These functionsinclude growth cone guidance, axonal pathfindin, and embryonicdevelopment. Therefore, the MOL5 nucleic acids and proteins are usefulin potential diagnostic and therapeutic applications and as a researchtool. These include serving as a specific or selective nucleic acid orprotein diagnostic and/or prognostic marker, wherein the presence oramount of the nucleic acid or the protein are to be assessed. These alsoinclude potential therapeutic applications such as the following: (i) aprotein therapeutic, (ii) a small molecule drug target, (iii) anantibody target (therapeutic, diagnostic, drug targeting/cytotoxicantibody), (iv) a nucleic acid useful in gene therapy (genedelivery/gene ablation), (v) an agent promoting tissue regeneration invitro and in vivo, and (vi) a biological defense weapon.

[0152] The MOL5 nucleic acids and proteins have applications in thediagnosis and/or treatment of various diseases and disorders. Forexample, the compositions of the present invention will have efficacyfor the treatment of patients suffering from: Rheumatoid arthritis (RA),CNS disorders, Alzheimer, Down syndrome, Schizophrenia, Parkinsonsdiseases as well as other diseases, disorders and conditions.

[0153] These materials are further useful in the generation ofantibodies that bind immuno-specifically to the novel MOL5 substancesfor use in therapeutic or diagnostic methods. These antibodies may begenerated according to methods known in the art, using prediction fromhydrophobicity charts, as described in the “Anti-MOLX Antibodies”section below. The disclosed MOL5 protein has multiple hydrophilicregions, each of which can be used as an immunogen. In one embodiment, acontemplated MOL5 epitope is from about amino acids 30 to 70. In anotherembodiment, a MOL5 epitope is from about amino acids 100 to 150. Inadditional embodiments, MOL5 epitopes are from about amino acids 175 to200, 220 to 450, 550 to 575, 590 to 610, and from about amino acids 675to 850. These novel proteins can also be used to develop assay systemsfor functional analysis.

[0154] MOL6

[0155] The disclosed novel kappa casein precursor-like MOL6 nucleic acidof 603 nucleotides (also referred to as GMAC060288_A) is shown in Table6A. An open reading begins with an ATG initiation codon at nucleotides31-33 and ends with a TAA codon at nucleotides 574-576. A putativeuntranslated region upstream from the initiation codon and downstreamfrom the termination codon are underlined in Table 6A, and the start andstop codons are in bold letters. TABLE 6A MOL6 Nucleotide Sequence (SEQID NO:19) TTTTTTTTAAATTTATCTTTAGGTGCAATAATGAAGAGTTTTCTTCTAGTTGTCAATGCCCTGGCATTAACCCTGCCTTTTTTGCTAGTGGAGGTTCAAAACCAGAAACAACCAGCATGCCATGAGAATGATGAAAGACCATTCTATCAGAAAACGTTCACATATGTCCCAATGTATTATGTGCAAAATAGCTATCTTTATTATGGACCCAATTTCTACAAACGTAGACCAGCTATAGCATTAAATAATCAATATGGGCTTCGCACATATTATGCAACCCAAGCTGTAGTTAGGGCACATGCCCAAATTCCTCACCGGCAATACCTGCCAAATAGCCACCACACTGTGGTACGTCGCCCAAACCTGCATCCATCATTTATTGCAATCCCCCCAAAGAAAATTCAGGATAAAATAATCATCCCTACCATCAATACCATTGCTACTGTTGAACCTACACCAGCTCCTGCCACTGAACCAACCGTGGACAGTGTAATCACTCCAGAAGCTTTTTCAGAGTCCATCATCACGAGCACCCCTGAGACAACCACAGTTGCAGTTACTCCACCTACGGCATAAAAACACCAAGGAAATATCAAAGAACAC

[0156] The MOL6 protein encoded by SEQ ID NO:20 has 181 amino acidresidues, and is presented using the one-letter code in Table 6B (SEQ IDNO:20). The Psort profile for MOL6 predicts that this sequence has asignal peptide and is likely to be localized outside the cell with acertainty of 0.8200. The most likely cleavage site for a peptide isbetween amino acids 24 and 25: VQN-QK based on the SignalP result. Themolecular weight of the MOL6 protein is 20424.3 Daltons. TABLE 6BEncoded MOL6 protein sequence. (SEQ ID NO:20)MKSFLLVVNALALTLPFLLVEVQNQKQPACHENDERPFYQKTFTYVPMYYVQNSYLYYGPNLYKRRPAIALNNQYGLRTYYATQAVVRAHAQIPQRQYLPNSHHTVVRRPNLHPSFIAIPPKKIQDKIIIPTINTIATVEPTPAPATEPTVDSVITPEAFSESIITSTPETTTVAVTPPTA

[0157] The disclosed nucleic acid sequence has 566 of 586 bases (96%)identical to a Homo sapiens kappa casein precursor mRNA (GENBANK-ID:ACC: 129004) (E value=9.8e⁻¹¹⁶)

[0158] The full amino acid sequence of MOL6 was found to have 165 of 182amino acid residues (90%) identical to, and 168 of 182 residues (92%)positive with, the 182 amino acid residue kappa casein precursor proteinfrom Homo sapiens (ptnr: SWISSPROT-ACC:P07498) (E value=3.0e⁻⁸³), 165 of182 amino acid residues (90%) identical to, and 168 of 182 residues(92%) positive with patp:AAR39351 Recombinant human kappa casein—Homosapiens having 182 aa (E value=3.0e⁻⁸³), and 165 of 182 amino acidresidues (90%) identical to, and 168 of 182 residues (92%) positive withpatp:AAR92150 Human milk kappa-casein having 182 amino acids (Evalue=3.0e⁻⁸³).

[0159] The global sequence homology (as defined by FASTA alignment withthe full length sequence of this protein) is 92.265% amino acid homologyand 91.160% amino acid identity. In addition, this protein contains thefollowing protein domains (as defined by Interpro) at the indicatednucleotide positions: casein-kappa (IPR000117) at amino acid positions 1to 181.

[0160] The full amino acid sequence of MOL6 was found to have homologywith several proteins, including those disclosed in the BLASTP data inTable 6C. TABLE 6C BLAST results for MOL6 Gene Index/ Protein/ LengthIdentity Positives Identifier Organism (aa) (%) (%) Expectgi|1705606|sp|P0749 KAPPA CASEIN 182 154/171 157/171 3e−59 8|CASK_HUMANPRECURSOR (90%) (91%) gi|4885161|ref|NP_0 casein, kappa [Homo 182153/171 156/171 9e−59 05203.1| sapiens] (89%) (90%) gi|186655|gb|AAA594kappa-casein [Homo 182 153/171 156/171 6e−55 56.1| sapiens] (89%) (90%)gi|13633560|ref|XP_(—) casein, kappa [Homo 182 144/171 147/171 3e−54003538.3| sapiens] (84%) (85%) gi|2493502|sp|P7913 KAPPA CASEIN 182102/178 118/178 2e−31 9|CASK_CAMDR PRECURSOR (57%) (65%)

[0161] This information is presented graphically in the multiplesequence alignment given in Table 6D (with MOL6 being shown on line 1)as a ClustalW analysis comparing MOL6 with related protein sequences.

[0162] Table 6E lists the domain description from DOMAIN analysisresults against MOL6. The region from amino acid residue 1 through 116(SEQ ID NO:20) most probably (E=2e⁻³⁶ contains a casein kappa domainfound in Kappa casein, aligned here in Table 6E. This indicates that theMOL6 sequence has properties similar to those of other proteins known tocontain this domain.

[0163] The above defined information for MOL6 suggests that this kappacasein precursor-like protein may function as a member of a “KappaCasein Precursor family”. Members of this family is found as anutritional component of human milk. Therefore, the novel nucleic acidsand proteins identified here may be useful in potential therapeuticapplications implicated in (but not limited to) various pathologies anddisorders as indicated below. The potential therapeutic applications forMOL6 include, but are not limited to: protein therapeutic, smallmolecule drug target, antibody target (therapeutic, diagnostic, drugtargeting/cytotoxic antibody), diagnostic and/or prognostic marker,kappa casein precursor therapy (kappa casein precursor delivery/kappacasein precursor ablation), research tools, tissue reKappa CaseinPrecursor ration in vivo and in vitro of all tissues and cell typescomposing (but not limited to) those defined here.

[0164] The MOL6 nucleic acids and proteins are useful in potentialtherapeutic applications implicated in nutritional deficiencies. It isused as a nutrient supplement in milk based products to provide asubstantial improvement of the nutritional and biological value of theformulae, making it closer in similarity to human milk. Kappa casein canalso be used as a pharmaceutical and/or other pathologies and disorders.For example, a cDNA encoding the kappa casein precursor-like protein maybe useful in kappa casein precursor therapy, and the kappa caseinprecursor-like protein may be useful when administered to a subject inneed thereof. By way of nonlimiting example, the compositions of thepresent invention will have efficacy for treatment of patients sufferingfrom nutritional deficiencies. MOL6, or fragments thereof, may furtherbe useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed.

[0165] These materials are further useful in the generation ofantibodies that bind immuno-specifically to the novel MOL6 substancesfor use in therapeutic or diagnostic methods. These antibodies may begenerated according to methods known in the art, using prediction fromhydrophobicity charts, as described in the “Anti-MOLX Antibodies”section below. The disclosed MOL6 protein has multiple hydrophilicregions, each of which can be used as an immunogen. In one embodiment, acontemplated MOL6 epitope is from about amino acids 30 to 125. Inanother embodiment, a MOL6 epitope is from about amino acids 140 to 160.These novel proteins can also be used to develop assay systems forfunctional analysis.

[0166] MOL7

[0167] A novel nucleic acid encoding a human Rh type Bglycoprotein-like-protein MOL7 was identified by TblastN using CuraGenCorporation's sequence file for MOL7 probes or homologs, and run againstthe Genomic Daily Files made available by GenBank. The disclosed novelMOL7 nucleic acid of 1765 nucleotides (also referred to as AF193808A) isshown in Table 7A.

[0168] An open reading frame begins with an ATG initiation codon atnucleotides 39-41 and ends with a TAA codon at nucleotides 1383-1385. Aputative untranslated region upstream from the initiation codon anddownstream from the termination codon are underlined in Table 7A, andthe start and stop codons are in bold letters. TABLE 7A MOL7 NucleotideSequence (SEQ ID NO:21) AAAGCCTGCGAGCGCCAGCCGAGATCGCATCCCAACCCATGGCCGGGTCTCCTAGCCGCGCCGCGGGCCGGCGACTGCAGCTTCCCCTGCTGTGCCTCTTCCTCCAGGGCGCCACTGCCGTCCTCTTTGCTGTCTTTGTCCGCTACAACCACAAAACCGACGCTGCCCTCTGGCACCGGAGCAACCACAGTAACGCGGACAATGAATTTTACTTTCGCTACCCAAGTTTCCAGGACGTGCATGCCATGGTCTTCGTGGGCTTTGACTTCCTCATGGTCTTCCTGCAGCGTTACGGCTTCAGCAGCGTGGGCTTCACCTTCCTCCTGGCCGCCTTTGCCCTGCAGTGGTCCACACTGGTCCAGCGCTTTCTCCACTCCTTCCACGGTGGCCACATCCATGTTGGCGTGGAGAGCATGATCAATGCTGACTTTTGTGCGGGGGCCGTGCTCATCTCCTTTGGTGCCGTCCTGGGCAAGACCGGGCCTACCCAGCTGCTGCTCATCGCCCTGCTCGACGTGGTGCTGTTTGGCATCAATGAGTTTGTGCTCCTTCATCTCCTGGGGGTGAGAGTCTGGGGACGGATTTCTAGGGTTATGTCTAGTACCATGCTGGAGAAGAGCAAGCACCGCCAGGGCTCCGTCTACCATTCAGACCTCTTCGCCATGATTGGTGGGACCATCTTCCTGTGGATCTTCTGGCCTAGCTTCAATGCTGCACTCACAGCGCTCGGGGCTGGGCAGCATCGGACGGCCCTCAACACATACTACTCCCTGGCTGCCAGCACCCTTGGCACCTTTGCCTTGTCAGCCCTTGTAGGGGAAGATGGGAGGCTTGACATGGTAGTCCACATCCAAAATGCAGCGCTGGCTGGAGGGGTTGTGGTGGGGACCTCAAGTGAAATGATGCTGACACCCTTTGGGGCTCTGGCAGCTGGCTTCTTGGCTGGGACTGTCTCCACGCTGGGGTACAAGTTCTTCACGCCCATCCTTGAATCAAAATTCAAAGTCCAAGACACATGTGGAGTCCACAACCTCCATGGGATGCCCCGGGTCCTGGGGGCCCTCCTGGGGGTCCTTGTCGCTGGACTTGCCACCCATGAACCTTACGGAGATGGGCTGGAGAGTGTGTTTCCACTCATAGCCGAGGGCCAGCGCAGTGCCACGTCACAGGCCATGCACCAGCTCTTCGGGCTGTTTGTCACACTGATGTTTGCCTCTGTGGGCGGGGGCCTTGGAGGTGGGCTCCTGCTGAAGCTACCCTTTCTGGACTCCCCCCCCGACTCCCAGCACTACGAGGACCAAGTTCACTGGCAGGTGGTGCCTGGCGAGCATGAGGATAAAGCCCAGAGACCTCTGAGGGTGGAGGACGCAGACACTCAGGCCTAACCCACTGCCAGCCCCTGAGAGGACACGCTCCTTTTCGAAGATGCTGACTGGCTGCTACTAGGAAGTTCTTTTTGAGCTCCCATTCCTCCAGCTGCAAGAAGGGAGCCATGAGCCAGAAGGAGGCCCCTTTCCACAGGCAGCGTCTCCACAGGGAGAGGGGCAACAGGAGGCTGGGAAATGGTGCGGAGTGGGGCCGTAACTGCGTACAATAGGGGGAACCTCACCAGATGCCCAACCCGACTGCCCTACCAGCCTGCACATGGGTAGAAGAGGCCAAATTGAGGCACCCAAGTGATCCACTGGCCCCACGTCACACAGTTACAGTGAAGCCCAAGCCAGGCCTGGTTGAGGGTGATAAACGCCACTGTCTTTAAGGAAAA

[0169] The MOL7 protein encoded by SEQ ID NO:21 has 448 amino acidresidues, and is presented using the one-letter code in Table 7B (SEQ IDNO:22). The SignalP, Psort and/or Hydropathy profile for MOL7 predictthat MOL7 has a signal peptide and is likely to be localized at theplasma membrane with a certainty of 0.6400. The SignalP shows a signalsequence is coded for with the most likely cleavage site being betweenamino acids 27 and 28: ATA-VL. This is typical of this type of membraneprotein. The molecular weight of the MOL7 protein is 48304.3 Daltons.TABLE 7B Encoded MOL7 protein sequence. (SEQ ID NO:22)MAGSPSRAAGRRLQLPLLCLFLQGATAVLFAVFVRYNHKTDAALWHRSNHSNADNEFYFRYPSFQDVHAMVFVGFDFLMVFLQRYGFSSVGFTFLLAAFALQWSTLVQGFLHSFHGGHIHVGVESMINADFCAGAVLISFGAVLGKTGPTQLLLMALLEVVLFGINEFVLLHLLGVRVWGGISRVMSSTMLEKSKHRQGSVYHSDLFAMIGGTIFLWIFWPSFNAALTALGAGQHRTALNTYYSLAASTLGTFALSALVGEDGRLDMVVHIQNAALAGGVVVGTSSEMNLTPFGALAAGFLAGTVSTLCYKFFTPTLESKFKVQDTCGVHNLHGMPGVLGALLGVLVAGLATHEAYGDGLESVFPLIAEGQRSATSQAMHQLFGLFVTLMFASVCGGLGGGLLLKLPFLDSPPDSQHYEDQVHWQVVPGEHEDKAQRPLRVEEADTQA

[0170] The nucleic acid sequence of MOL7 was found to have 680 of 815bases (83) identical to a mouse Rh type b glycoprotein mRNA(GENBANK-ID:AF193808jacc:AF193808).

[0171] The full amino acid sequence of MOL7 was found to have 363 of 448amino acid residues (81%) identical to, and 399 of 448 residues (89%)positive with, the 455 amino acid residue mouse RH TYPE B GLYCOPROTEIN(ptnr: SPTREMBL-ACC:Q9QXP1)

[0172] The full amino acid sequence of MOL7 was found to have homologywith several proteins, including those disclosed in the BLASTP data inTable 7C. TABLE 7C BLAST results for MOL7 Gene Index/ Protein/ LengthIdentity Positives Identifier Organism (aa) (%) (%) Expectgi|9966891|ref|NP_0 Rh type B 458 433/462 435/462 0.0 65140.1|glycoprotein (93%) (93%) [Homo sapiens] gi|14346006|gb|AAK1 Rh type B458 429/462 431/462 0.0 5395.1| (AY013268) glycoprotein [Pan (92%) (92%)troglodytes] gi|14486159|gb|AAK1 Rh type B 458 384/462 409/462 0.04651.1| (AY013261) glycoprotein [Sus (83%) (88%) scrofa]gi|10946710|ref|NP_(—) Rhesus blood 455 362/452 398/452 e−177 067350.1|group-associated (80%) (87%) B glycoprotein; Rh type B glycoprotein [Musmusculus] gi|14486161|gb|AAK1 Rh type B 458 373/462 404/462 e−1764652.1| (AY013262) glycoprotein (80%) (86%) [Oryctolagus cuniculus]

[0173] This information is presented graphically in the multiplesequence alignment given in Table 7D (with MOL7 being shown on line 1)as a ClustalW analysis comparing MOL7 with related protein sequences.

[0174] Table 7E lists the domain description from DOMAIN analysisresults against MOL7. The region from amino acid residue 25 through 336(SEQ ID NO:22) most probably (E=le-33) contains an ammonium transporterdomain found in Ammonium transporters, aligned here in Table 7E. Thisindicates that the MOL7 sequence has properties similar to those ofother proteins known to contain this domain.

[0175] TaqMan Data

[0176] Example 2 shows a TaqMan expression profile in 41 normal humantissues and 55 human cancer cell lines. The MOL7 gene is expressed innormal tissues, specifically lung, colon, small intestine, and prostate,and is lost in cancer cell lines.

[0177] Example 2 also shows replicate TaqMan expression results in tumortissues that are often matched with normal adjacent tissue (NAT), asdefined by the operating surgeon. The results reveal that the MOL7 humanRh type B glycoprotein is overexpressed in kidney tumors compared withtheir NAT and normal tissues.

[0178] Chromosomal Localization:

[0179] This gene belongs to genomic DNA GenBank AL139130 which maps tochromosome 1.

[0180] Tissue Expression:

[0181] MOL7 has been found to be expressed in Renal clear cell carcinomaby EST analysis. Genbank EST AI310325 has 100% identity with novel Rhtype B glycoprotein and was obtained from 2 pooled tumors (clear celltype). Kidney, AI925934 has 100% identity with novel Rh type Bglycoprotein and was obtained from Kidney. Fetal spleen R83833 andAI022447 have 96% identity to novel Rh type B glycoprotein and wereobtained from Fetal spleen. The tissue expression profile of was alsodetermined by TaqMan.

[0182] Uses of the Compositions of the Invention

[0183] The expression pattern, map location and protein similarityinformation for the MOL7 suggest that this gene may function as “an Rhfamily” member. Therefore, the MOL7 nucleic acids and proteins areuseful in potential therapeutic applications implicated in variouspathologies/disorders described and/or other pathologies/disorders

[0184] Potential therapeutic uses for MOL7 include: Protein therapeutic,Small molecule drug target, Antibody target (Therapeutic, Diagnostic,Drug targeting/Cytotoxic antibody), Diagnostic and/or prognostic marker,Gene therapy (gene delivery/gene ablation), Research tools, Tissueregeneration in vitro and in vivo (regeneration for all these tissuesand cell types composing these tissues and cell types derived from thesetissues)

[0185] The MOL7 nucleic acids and proteins are useful in potentialtherapeutic applications implicated in various names ofpathologies/disorders described below and/or other pathologiesdisorders. For example, a cDNA encoding the RH TYPE B GLYCOPROTEIN—likeprotein may be useful in gene therapy, and the RH TYPE BGLYCOPROTEIN-like protein may be useful when administered to a subjectin need thereof. By way of nonlimiting example, the compositions of thepresent invention will have efficacy for treatment of patients sufferingfrom the pathologies described above. The novel nucleic acid encodingMOL7, or fragments thereof, may further be useful in diagnosticapplications, wherein the presence or amount of the nucleic acid or theprotein are to be assessed.

[0186] These materials are further useful in the generation ofantibodies that bind immuno-specifically to the novel MOL7 substancesfor use in therapeutic or diagnostic methods. These antibodies may begenerated according to methods known in the art, using prediction fromhydrophobicity charts, as described in the “Anti-MOLX Antibodies”section below. The disclosed MOL7 protein has multiple hydrophilicregions, each of which can be used as an immunogen. In one embodiment, acontemplated MOL7 epitope is from about amino acids 40 to 80. In anotherembodiment, a MOL7 epitope is from about amino acids 160 to 190. Inadditional embodiments, MOL7 epitopes are from about amino acids 175 to225, 235 to 250, 325 to 345, 360 to 380, and from about amino acids 400to 450. These novel proteins can also be used to develop assay systemsfor functional analysis.

[0187] MOL8

[0188] A novel human Noelin-2-like nucleic acid was identified byTblastN using CuraGen Corporation's sequence file. The disclosed novelMOL8 nucleic acid of 1399 nucleotides (also referred to as SC84366578_A)is shown in Table 8A. An open reading frame begins with an ATGinitiation codon at nucleotides 14-16 and ends with a TAG codon atnucleotides 1391-1393. A putative untranslated region downstream fromthe termination codon are underlined in Table 8A, and the start and stopcodons are in bold letters. TABLE 8A MOL8 Nucleotide Sequence (SEQ IDNO:23) TGTTTTACTTGAAATGCTACAAACCAACACTCTTTTTATCCTAAAACAGGAGTCTGTGTTTTATGTTTCCCTTTGGTTTCCTCAGACTCAGATTAGTCCTAAAGAAGGGTGGCAGGTGTACAGCTCAGCTCAGGATCCTGATGGGCGGTGCATTTGCACAGTTGTTGCTCCAGAACAAAACCTGTGTTCCCGGGATGCCAAAAGCAGGCAACTTCGCCAACTACTGGAAAAGGTACAGAACATGTCCCAGTCTATTGAAGTCTTAAACTTGAGAACTCAGAGAGATTTCCAATATGTTTTAAAAATGGAAACCCAAATGAAAGGGCTGAAGGCAAAATTTCGGCAGATTGAAGATGATCGAAAGACACTTATGACCAAGCATTTTCAGCAGGAGTTGAAAGAGAAAATGGACGAGCTCCTGCCTTTGATCCCCGTGCTGGAACAGTGCAAAACAGATGCTAAGTTCATCACCCAGTTCAAGGAGGAAATAAGGAATCTGTCTGCTGTCCTCACTGGTATTCAGGAGGAAATTGGTGCCTATGACTACGAGGAACTACACCAAAGAGTGCTGAGCTTGGAAACAAGACTTCGTGACTGCATGAAAAAGCTATGTGGCAAACTGATGAAAATCACAGGCCCAGTTACAGTCAAGACATCTGGAACCCGATTTGGTGCTTGGATGACAGACCCTTTAGCATCTGAGAAAAACAACAGAGTATGGTACATGGACAGTTATACTAACAATAAAATTGTTCGTGAATACAAATCAATTGCAGACTTTGTCAGTGGGGCTGAATCAAGGACATACAACCTTCCTTTCAAGTGGGCAGGAACTAACCATGTTGTCTACAATGGCTCACTCTATTTTAACAAGTATCAGAGTAATATCATCATCAAATACAGCTTTGATATGGGGAGAGTGCTTGCCCAACGAAGCCTGGAGTATGCTGGTTTTCATAATGTTTACCCCTACACATGGGGTGGATTCTCTGACATCGACCTAATGGCTGATGAAATCGGGCTGTGGGCTGTGTATGCAACTAACCAGAATGCAGGCAATATTGTCATCAGCCAACTTAACCAAGATACCTTGGAGGTGATGAAGAGCTGGAGCACTGGCTACCCCAAGAGAAGTGCAGGGGAATCTTTCATGATCTGTGGGACACTGTATGTCACCAACTCCCACTTAACTGGAGCCAAGGTGTATTATTCCTATTCCACCAAAACCTCCACATATGAGTACACAGACATTCCCTTCCATAACCAATACTTTCACATATCCATGCTTGACTACAATGCAAGAGATCGAGCTCTCTATGCCTGGAACAATGGCCACCAGGTGCTGTTCAATGTCACCCTTTTCCATATCATCAAGACAGAGGATGACACATAG GCAAAT

[0189] The MOL8 protein encoded by SEQ ID NO:23 has 459 amino acidresidues, and is presented using the one-letter code in Table 8B (SEQ IDNO:24). The SignalP, Psort and/or Hydropathy profile for MOL8 predictthat MOL8 has no signal peptide and is likely to be localized at themicrobody (peroxisome) with a certainty of 0.5616. The molecular weightof the MOL8 protein is 53275.2 Daltons. TABLE 8B Encoded MOL8 proteinsequence. (SEQ ID NO:24)MLQTNTLFILKQESVFYVSLWFPQTQISPKEGWQVYSSAQDPDGRCICTVVAPEQNLCSRDAKSRQLRQLLEKVQNMSQSIEVLNLRTQRDFQYVLKMETQMKGLKAKFRQIEDDRKTLMTKHFQQELKEKMDELLPLIPVLEQCKTDAKFITQFKEEIRNLSAVLTGIQEEIGAYDYEELHQRVLSLETRLRDCMKKLCGKLMKITGPVTVKTSGTRFGAWMTDPLASEKNNRVWYMDSYTNNKIVREYKSIADFVSGAESRTYNLPFKWAGTNHVVYNGSLYFNKYQSNIIIKYSFDMGRVLAQRSLEYAGFHNVYPYTWGGFSDIDLMADEIGLWAVYATNQNAGNIVISQLNQDTLEVMKSWSTGYPKRSAGESFMICGTLYVTNSHLTGAKVYYSYSTKTSTYEYTDIPFHNQYFHISMLDYNARDRALYAWNNGHQVLFNVTLFHIIKTEDDT

[0190] The nucleotide sequence of MOL8 has 889 of 1286 bases (69%)identical to a Gallus gallus NOELIN-2 mRNA (GENBANK-ID: AF239804). Thefull amino acid sequence of the protein of the invention was found tohave 288 of 448 amino acid residues (64%) identical to, and 367 of 448residues (80%) positive with, the 457 amino acid residue NOELIN-2protein from Gallus gallus (Chicken) (ptnr:SPTREMBL-ACC: AAF43715), and439 of 459 amino acid residues (95%) identical to, and 442 of 459residues (96%) positive with, the 458 amino acid residue patp:AAB74696Human membrane associated protein MEMAP-2.

[0191] The global sequence homology (as defined by FASTA alignment withthe full length sequence of this protein) is 74% amino acid homology and65% amino acid identity. In addition, this protein contains thefollowing protein domain (as defined by Pfam) at the indicatednucleotide positions: Olfactomedin-like domain (PF02191) at amino acidpositions 201 to 451.

[0192] The full amino acid sequence of MOL8 was found to have homologywith several proteins including those disclosed in the BLASTP data inTable 8C. TABLE 8C BLAST results for MOL8 Gene Index/ Protein/ LengthIdentity Positives Identifier Organism (aa) (%) (%) Expectgi|3024210|sp|Q6260 NOELIN PRECURSOR 485 285/431 355/431 e−1729|NOE1_RAT (NEURONAL (66%) (82%) OLFACTOMEDIN- RELATED ER LOCALIZEDPROTEIN) (PANCORTIN) (1B426B) gi|13124385|sp|Q9IA NOELIN PRECURSOR 485284/431 357/431 e−171 K4|NOE1_CHICK (NEURONAL (65%) (81%) OLFACTOMEDIN-RELATED ER LOCALIZED PROTEIN) (PANCORTIN) gi|9506929|ref|NP_0olfactomedin 485 284/431 354/431 e−171 62371.1| related ER (65%) (81%)localized protein [Mus musculus] gi|7248902|gb|AAF43 NOELIN-2 [Gallus457 284/431 357/431 e−171 715.1|AF239804_1 gallus] (65%), (81%)(AF239804) gi|2143875|pir||I73 neuronal 457 285/431 355/431 e−171 636olfactomedin- (66%) (82%) related ER localized protein - rat

[0193] Homology between MOL8 and other proteins are presentedgraphically in the multiple 15 sequence alignment given in Table 8D(with MOL8 being shown on line 1) as a ClustalW analysis comparing MOL8with related protein sequences.

[0194] Table 8E lists the domain description from DOMAIN analysisresults against MOL8. The region from amino acid residue 201 through 457(SEQ ID NO:24) most probably (E=4e⁻⁸⁵) Contains a Olfactomedin-likedomain, aligned in Table 8E. This indicates that the MOL8 sequence hasproperties similar to those of other proteins known to contain thisdomain.

[0195] Uses of the Compositions of the Invention

[0196] The above defined information for MOL8 suggests that thisNoelin-2-like protein may function as a member of a “Noelin-2 family”.This family is involved in neural crest development, and otherdevelopmental processes. Therefore, the novel nucleic acids and proteinsidentified here may be useful in potential therapeutic applicationsimplicated in (but not limited to) various pathologies and disorders asindicated below. The potential therapeutic applications for MOL8include, but are not limited to: protein therapeutic, small moleculedrug target, antibody target (therapeutic, diagnostic, drugtargeting/cytotoxic antibody), diagnostic and/or prognostic marker, genetherapy (gene delivery/gene ablation), research tools, tissueregeneration in vivo and in vitro of all tissues and cell typescomposing (but not limited to) those defined here.

[0197] The MOL8 nucleic acids and proteins are useful in potentialtherapeutic applications implicated in neural crest development in earlyembryonic stage. For example, a cDNA encoding the Noelin-2-like proteinmay be useful in gene therapy, and the Noelin-2-like protein may beuseful when administered to a subject in need thereof. By way ofnonlimiting example, the compositions of the present invention will haveefficacy for treatment of patients suffering from primary open-angleglaucoma (POAG), and bone disorders, hematopoietic disorders,neuro-developmental disorders, cancer, autoimmune disorders, psychiatricdisorders. The novel nucleic acid encoding MOL8, or fragments thereof,may further be useful in diagnostic applications, wherein the presenceor amount of the nucleic acid or the protein are to be assessed.

[0198] These materials are further useful in the generation ofantibodies that bind immuno-specifically to the novel MOL8 substancesfor use in therapeutic or diagnostic methods. These antibodies may begenerated according to methods known in the art, using prediction fromhydrophobicity charts, as described in the “Anti-MOLX Antibodies”section below. The disclosed MOL8 protein has multiple hydrophilicregions, each of which can be used as an immunogen. In one embodiment, acontemplated MOL8 epitope is from about amino acids 20 to 50. In anotherembodiment, a MOL8 epitope is from about amino acids 50 to 125. Inadditional embodiments, MOL8 epitopes are from about amino acids 140 to210, 225 to 320, 350 to 375, and from about amino acids 380 to 440.These novel proteins can also be used to develop assay systems forfunctional analysis. TABLE 9 Summary Of Nucleic Acids And Proteins OfThe Invention Nucleic Amino Acid Acid SEQ ID SEQ ID Name Tables Clone;Description of Homolog NO NO MOL1 1A, 1B, MOL1a: SC29674552_EXT 1 2 1D,1E MOL1b: CG56250-02 3 4 MOL2 2A, 2B MOL2: SC98428706_EXT 5 6 MOL3 3A,3B MOL3a: SC85516573_EXT 7 8 3D, 3E MOL3b: CG53027-02 9 10 MOL4 4A, 4B,MOL4: SC_111750277_A 11 12 MOL5 5A, 5B, MOL5a: SC20422974_A 13 14 5C,5D, MOL5b: SC14998905_EXT 15 16 5E, 5F MOLc: CG50907-02 17 18 MOL6 6A,6B MOL6: GMAC060288_A 19 20 MOL7 7A, 7B MOL7: AF193808A 21 22 MOL8 8A,8B MOL8: SC84366578_A 23 24

[0199] MOLX Nucleic Acids and Polypeptides

[0200] One aspect of the invention pertains to isolated nucleic acidmolecules that encode MOLX polypeptides or biologically active portionsthereof. Also included in the invention are nucleic acid fragmentssufficient for use as hybridization probes to identify MOLX-encodingnucleic acids (e.g., MOLX mRNAs) and fragments for use as PCR primersfor the amplification and/or mutation of MOLX nucleic acid molecules. Asused herein, the term “nucleic acid molecule” is intended to include DNAmolecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA),analogs of the DNA or RNA generated using nucleotide analogs, andderivatives, fragments and homologs thereof. The nucleic acid moleculemay be single-stranded or double-stranded, but preferably is compriseddouble-stranded DNA.

[0201] An MOLX nucleic acid can encode a mature MOLX polypeptide. Asused herein, a “mature” form of a polypeptide or protein disclosed inthe present invention is the product of a naturally occurringpolypeptide or precursor form or proprotein. The naturally occurringpolypeptide, precursor or proprotein includes, by way of nonlimitingexample, the full-length gene product, encoded by the correspondinggene. Alternatively, it may be defined as the polypeptide, precursor orproprotein encoded by an ORF described herein. The product “mature” formarises, again by way of nonlimiting example, as a result of one or morenaturally occurring processing steps as they may take place within thecell, or host cell, in which the gene product arises. Examples of suchprocessing steps leading to a “mature” form of a polypeptide or proteininclude the cleavage of the N-terminal methionine residue encoded by theinitiation codon of an ORF, or the proteolytic cleavage of a signalpeptide or leader sequence. Thus a mature form arising from a precursorpolypeptide or protein that has residues 1 to N, where residue 1 is theN-terminal methionine, would have residues 2 through N remaining afterremoval of the N-terminal methionine. Alternatively, a mature formarising from a precursor polypeptide or protein having residues 1 to N,in which an N-terminal signal sequence from residue 1 to residue M iscleaved, would have the residues from residue M+1 to residue Nremaining. Further as used herein, a “mature” form of a polypeptide orprotein may arise from a step of post-translational modification otherthan a proteolytic cleavage event. Such additional processes include, byway of non-limiting example, glycosylation, myristoylation orphosphorylation. In general, a mature polypeptide or protein may resultfrom the operation of only one of these processes, or a combination ofany of them.

[0202] The term “probes”, as utilized herein, refers to nucleic acidsequences of variable length, preferably between at least about 10nucleotides (nt), 100 nt, or as many as approximately, e.g., 6,000 nt,depending upon the specific use. Probes are used in the detection ofidentical, similar, or complementary nucleic acid sequences. Longerlength probes are generally obtained from a natural or recombinantsource, are highly specific, and much slower to hybridize thanshorter-length oligomer probes. Probes may be single- or double-strandedand designed to have specificity in PCR, membrane-based hybridizationtechnologies, or ELISA-like technologies.

[0203] The term “isolated” nucleic acid molecule, as utilized herein, isone, which is separated from other nucleic acid molecules which arepresent in the natural source of the nucleic acid. Preferably, an“isolated” nucleic acid is free of sequences which naturally flank thenucleic acid (i.e., sequences located at the 5′- and 3′-termini of thenucleic acid) in the genomic DNA of the organism from which the nucleicacid is derived. For example, in various embodiments, the isolated MOLXnucleic acid molecules can contain less than about 5 kb, 4 kb, 3 kb, 2kb, 1 kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally flankthe nucleic acid molecule in genomic DNA of the cell/tissue from whichthe nucleic acid is derived (e.g., brain, heart, liver, spleen, etc.).Moreover, an “isolated” nucleic acid molecule, such as a cDNA molecule,can be substantially free of other cellular material or culture mediumwhen produced by recombinant techniques, or of chemical precursors orother chemicals when chemically synthesized.

[0204] A nucleic acid molecule of the invention, e.g., a nucleic acidmolecule having the nucleotide sequence of SEQ ID NOS:1, 3, 5, 7, 9, 11,13, 15, 17, 19, 21, and 23, or a complement of this aforementionednucleotide sequence, can be isolated using standard molecular biologytechniques and the sequence information provided herein. Using all or aportion of the nucleic acid sequence of SEQ ID NOS: 1, 3, 5, 7, 9, 11,13, 15, 17, 19, 21, and 23 as a hybridization probe, MOLX molecules canbe isolated using standard hybridization and cloning techniques (e.g.,as described in Sambrook, et al., (eds.), MOLECULAR CLONING: ALABORATORY MANUAL 2^(nd) Ed., Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y., 1989; and Ausubel, et al., (eds.), CURRENTPROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, N.Y.,1993.)

[0205] A nucleic acid of the invention can be amplified using cDNA, mRNAor alternatively, genomic DNA, as a template and appropriateoligonucleotide primers according to standard PCR amplificationtechniques. The nucleic acid so amplified can be cloned into anappropriate vector and characterized by DNA sequence analysis.Furthermore, oligonucleotides corresponding to MOLX nucleotide sequencescan be prepared by standard synthetic techniques, e.g., using anautomated DNA synthesizer.

[0206] As used herein, the term “oligonucleotide” refers to a series oflinked nucleotide residues, which oligonucleotide has a sufficientnumber of nucleotide bases to be used in a PCR reaction. A shortoligonucleotide sequence may be based on, or designed from, a genomic orcDNA sequence and is used to amplify, confirm, or reveal the presence ofan identical, similar or complementary DNA or RNA in a particular cellor tissue. Oligonucleotides comprise portions of a nucleic acid sequencehaving about 10 nt, 50 nt, or 100 nt in length, preferably about 15 ntto 30 nt in length. In one embodiment of the invention, anoligonucleotide comprising a nucleic acid molecule less than 100 nt inlength would further comprise at least 6 contiguous nucleotides of SEQID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23, or a complementthereof. Oligonucleotides may be chemically synthesized and may also beused as probes.

[0207] In another embodiment, an isolated nucleic acid molecule of theinvention comprises a nucleic acid molecule that is a complement of thenucleotide sequence shown in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17,19, 21, and 23, or a portion of this nucleotide sequence (e.g., afragment that can be used as a probe or primer or a fragment encoding abiologically-active portion of an MOLX polypeptide). A nucleic acidmolecule that is complementary to the nucleotide sequence shown in SEQID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23 is one that issufficiently complementary to the nucleotide sequence shown in SEQ IDNOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23 that it can hydrogenbond with little or no mismatches to the nucleotide sequence shown SEQID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23, thereby forming astable duplex.

[0208] As used herein, the term “complementary” refers to Watson-Crickor Hoogsteen base pairing between nucleotides units of a nucleic acidmolecule, and the term “binding” means the physical or chemicalinteraction between two polypeptides or compounds or associatedpolypeptides or compounds or combinations thereof. Binding includesionic, non-ionic, van der Waals, hydrophobic interactions, and the like.A physical interaction can be either direct or indirect. Indirectinteractions may be through or due to the effects of another polypeptideor compound. Direct binding refers to interactions that do not takeplace through, or due to, the effect of another polypeptide or compound,but instead are without other substantial chemical intermediates.

[0209] Fragments provided herein are defined as sequences of at least 6(contiguous) nucleic acids or at least 4 (contiguous) amino acids, alength sufficient to allow for specific hybridization in the case ofnucleic acids or for specific recognition of an epitope in the case ofamino acids, respectively, and are at most some portion less than a fulllength sequence. Fragments may be derived from any contiguous portion ofa nucleic acid or amino acid sequence of choice. Derivatives are nucleicacid sequences or amino acid sequences formed from the native compoundseither directly or by modification or partial substitution. Analogs arenucleic acid sequences or amino acid sequences that have a structuresimilar to, but not identical to, the native compound but differs fromit in respect to certain components or side chains. Analogs may besynthetic or from a different evolutionary origin and may have a similaror opposite metabolic activity compared to wild type. Homologs arenucleic acid sequences or amino acid sequences of a particular gene thatare derived from different species.

[0210] Derivatives and analogs may be full length or other than fulllength, if the derivative or analog contains a modified nucleic acid oramino acid, as described below. Derivatives or analogs of the nucleicacids or proteins of the invention include, but are not limited to,molecules comprising regions that are substantially homologous to thenucleic acids or proteins of the invention, in various embodiments, byat least about 70%, 80%, or 95% identity (with a preferred identity of80-95%) over a nucleic acid or amino acid sequence of identical size orwhen compared to an aligned sequence in which the alignment is done by acomputer homology program known in the art, or whose encoding nucleicacid is capable of hybridizing to the complement of a sequence encodingthe aforementioned proteins under stringent, moderately stringent, orlow stringent conditions. See e.g. Ausubel, et al., CURRENT PROTOCOLS INMOLECULAR BIOLOGY, John Wiley & Sons, New York, N.Y., 1993, and below.

[0211] A “homologous nucleic acid sequence” or “homologous amino acidsequence,” or variations thereof, refer to sequences characterized by ahomology at the nucleotide level or amino acid level as discussed above.Homologous nucleotide sequences encode those sequences coding forisoforms of MOLX polypeptides. Isoforms can be expressed in differenttissues of the same organism as a result of, for example, alternativesplicing of RNA. Alternatively, isoforms can be encoded by differentgenes. In the invention, homologous nucleotide sequences includenucleotide sequences encoding for an MOLX polypeptide of species otherthan humans, including, but not limited to: vertebrates, and thus caninclude, e.g., frog, mouse, rat, rabbit, dog, cat cow, horse, and otherorganisms. Homologous nucleotide sequences also include, but are notlimited to, naturally occurring allelic variations and mutations of thenucleotide sequences set forth herein. A homologous nucleotide sequencedoes not, however, include the exact nucleotide sequence encoding humanMOLX protein. Homologous nucleic acid sequences include those nucleicacid sequences that encode conservative amino acid substitutions (seebelow) in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23, aswell as a polypeptide possessing MOLX biological activity. Variousbiological activities of the MOLX proteins are described below.

[0212] An MOLX polypeptide is encoded by the open reading frame (“ORF”)of an MOLX nucleic acid. An ORF corresponds to a nucleotide sequencethat could potentially be translated into a polypeptide. A stretch ofnucleic acids comprising an ORF is uninterrupted by a stop codon. An ORFthat represents the coding sequence for a full protein begins with anATG “start” codon and terminates with one of the three “stop” codons,namely, TAA, TAG, or TGA. For the purposes of this invention, an ORF maybe any part of a coding sequence, with or without a start codon, a stopcodon, or both. For an ORF to be considered as a good candidate forcoding for a boinafide cellular protein, a minimum size requirement isoften set, e.g., a stretch of DNA that would encode a protein of 50amino acids or more.

[0213] The nucleotide sequences determined from the cloning of the humanMOLX genes allows for the generation of probes and primers designed foruse in identifying and/or cloning MOLX homologues in other cell types,e.g. from other tissues, as well as MOLX homologues from othervertebrates. The probe/primer typically comprises substantially purifiedoligonucleotide. The oligonucleotide typically comprises a region ofnucleotide sequence that hybridizes under stringent conditions to atleast about 12, 25, 50, 100, 150, 200, 250, 300, 350 or 400 consecutivesense strand nucleotide sequence of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13,15, 17, 19, 21, and 23; or an anti-sense strand nucleotide sequence ofSEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23; or of anaturally occurring mutant of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17,19, 21, and 23.

[0214] Probes based on the human MOLX nucleotide sequences can be usedto detect transcripts or genomic sequences encoding the same orhomologous proteins. In various embodiments, the probe further comprisesa label group attached thereto, e.g. the label group can be aradioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor.Such probes can be used as a part of a diagnostic test kit foridentifying cells or tissues which mis-express an MOLX protein, such asby measuring a level of an MOLX-encoding nucleic acid in a sample ofcells from a subject e.g., detecting MOLX mRNA levels or determiningwhether a genomic MOLX gene has been mutated or deleted.

[0215] “A polypeptide having a biologically-active portion of an MOLXpolypeptide” refers to polypeptides exhibiting activity similar, but notnecessarily identical to, an activity of a polypeptide of the invention,including mature forms, as measured in a particular biological assay,with or without dose dependency. A nucleic acid fragment encoding a“biologically-active portion of MOLX” can be prepared by isolating aportion SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23 thatencodes a polypeptide having an MOLX biological activity (the biologicalactivities of the MOLX proteins are described below), expressing theencoded portion of MOLX protein (e.g., by recombinant expression invitro) and assessing the activity of the encoded portion of MOLX.

[0216] MOLX Nucleic Acid and Polypeptide Variants

[0217] The invention further encompasses nucleic acid molecules thatdiffer from the nucleotide sequences shown SEQ ID NOS: 1, 3, 5, 7, 9,11, 13, 15, 17, 19, 21, and 23 due to degeneracy of the genetic code andthus encode the same MOLX proteins as that encoded by the nucleotidesequences shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and23. In another embodiment, an isolated nucleic acid molecule of theinvention has a nucleotide sequence encoding a protein having an aminoacid sequence shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20,22, and 24.

[0218] In addition to the human MOLX nucleotide sequences shown in SEQID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23 it will beappreciated by those skilled in the art that DNA sequence polymorphismsthat lead to changes in the amino acid sequences of the MOLXpolypeptides may exist within a population (e.g., the human population).Such genetic polymorphism in the MOLX genes may exist among individualswithin a population due to natural allelic variation. As used herein,the terms “gene” and “recombinant gene” refer to nucleic acid moleculescomprising an open reading frame (ORF) encoding an MOLX protein,preferably a vertebrate MOLX protein. Such natural allelic variationscan typically result in 1-5% variance in the nucleotide sequence of theMOLX genes. Any and all such nucleotide variations and resulting aminoacid polymorphisms in the MOLX polypeptides, which are the result ofnatural allelic variation and that do not alter the functional activityof the MOLX polypeptides, are intended to be within the scope of theinvention.

[0219] Moreover, nucleic acid molecules encoding MOLX proteins fromother species, and thus that have a nucleotide sequence that differsfrom the human sequence SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19,21, and 23 are intended to be within the scope of the invention. Nucleicacid molecules corresponding to natural allelic variants and homologuesof the MOLX cDNAs of the invention can be isolated based on theirhomology to the human MOLX nucleic acids disclosed herein using thehuman cDNAs, or a portion thereof, as a hybridization probe according tostandard hybridization techniques under stringent hybridizationconditions.

[0220] Accordingly, in another embodiment, an isolated nucleic acidmolecule of the invention is at least 6 nucleotides in length andhybridizes under stringent conditions to the nucleic acid moleculecomprising the nucleotide sequence of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13,15, 17, 19, 21, and 23. In another embodiment, the nucleic acid is atleast 10, 25, 50, 100, 250, 500, 750, 1000, 1500, or 2000 or morenucleotides in length. In yet another embodiment, an isolated nucleicacid molecule of the invention hybridizes to the coding region. As usedherein, the term “hybridizes under stringent conditions” is intended todescribe conditions for hybridization and washing under which nucleotidesequences at least 60% homologous to each other typically remainhybridized to each other.

[0221] Homologs (i.e., nucleic acids encoding MOLX proteins derived fromspecies other than human) or other related sequences (e.g., paralogs)can be obtained by low, moderate or high stringency hybridization withall or a portion of the particular human sequence as a probe usingmethods well known in the art for nucleic acid hybridization andcloning.

[0222] As used herein, the phrase “stringent hybridization conditions”refers to conditions under which a probe, primer or oligonucleotide willhybridize to its target sequence, but to no other sequences. Stringentconditions are sequence-dependent and will be different in differentcircumstances. Longer sequences hybridize specifically at highertemperatures than shorter sequences. Generally, stringent conditions areselected to be about 5° C. lower than the thermal melting point (Tm) forthe specific sequence at a defined ionic strength and pH. The Tm is thetemperature (under defined ionic strength, pH and nucleic acidconcentration) at which 50% of the probes complementary to the targetsequence hybridize to the target sequence at equilibrium. Since thetarget sequences are generally present at excess, at Tm, 50% of theprobes are occupied at equilibrium. Typically, stringent conditions willbe those in which the salt concentration is less than about 1.0 M sodiumion, typically about 0.01 to 1.0 M sodium ion (or other salts) at pH 7.0to 8.3 and the temperature is at least about 30° C. for short probes,primers or oligonucleotides (e.g., 10 nt to 50 nt) and at least about60° C. for longer probes, primers and oligonucleotides. Stringentconditions may also be achieved with the addition of destabilizingagents, such as formamide.

[0223] Stringent conditions are known to those skilled in the art andcan be found in Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULARBIOLOGY, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. Preferably, theconditions are such that sequences at least about 65%, 70%, 75%, 85%,90%, 95%, 98%, or 99% homologous to each other typically remainhybridized to each other. A non-limiting example of stringenthybridization conditions are hybridization in a high salt buffercomprising 6×SSC, 50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02%Ficoll, 0.02% BSA, and 500 mg/ml denatured salmon sperm DNA at 65° C.,followed by one or more washes in 0.2×SSC, 0.01% BSA at 50° C. Anisolated nucleic acid molecule of the invention that hybridizes understringent conditions to the sequences of SEQ ID NOS: 1, 3, 5, 7, 9, 11,13, 15, 17, 19, 21, and 23 corresponds to a naturally-occurring nucleicacid molecule. As used herein, a “naturally-occurring” nucleic acidmolecule refers to an RNA or DNA molecule having a nucleotide sequencethat occurs in nature (e.g., encodes a natural protein).

[0224] In a second embodiment, a nucleic acid sequence that ishybridizable to the nucleic acid molecule comprising the nucleotidesequence of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23 orfragments, analogs or derivatives thereof, under conditions of moderatestringency is provided. A non-limiting example of moderate stringencyhybridization conditions are hybridization in 6×SSC, 5× Denhardt'ssolution, 0.5% SDS and 100 mg/ml denatured salmon sperm DNA at 55° C.,followed by one or more washes in 1×SSC, 0.1% SDS at 37° C. Otherconditions of moderate stringency that may be used are well-known withinthe art. See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS INMOLECULAR BIOLOGY, John Wiley & Sons, NY, and Kriegler, 1990; GENETRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY.

[0225] In a third embodiment, a nucleic acid that is hybridizable to thenucleic acid molecule comprising the nucleotide sequences of SEQ IDNOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23 or fragments, analogsor derivatives thereof, under conditions of low stringency, is provided.A non-limiting example of low stringency hybridization conditions arehybridization in 35% formamide, 5×SSC, 50 mM Tris-HCl (pH 7.5), 5 mMEDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 mg/ml denatured salmonsperm DNA, 10% (wt/vol) dextran sulfate at 40° C., followed by one ormore washes in 2×SSC, 25 mM Tris-HCl (pH 7.4), 5 mM EDTA, and 0.1% SDSat 50° C. Other conditions of low stringency that may be used are wellknown in the art (e.g., as employed for cross-species hybridizations).See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULARBIOLOGY, John Wiley & Sons, NY, and Kriegler, 1990, GENE TRANSFER ANDEXPRESSION, A LABORATORY MANUAL, Stockton Press, NY; Shilo and Weinberg,1981. Proc Natl Acad Sci USA 78: 6789-6792.

[0226] Conservative Mutations

[0227] In addition to naturally-occurring allelic variants of MOLXsequences that may exist in the population, the skilled artisan willfurther appreciate that changes can be introduced by mutation into thenucleotide sequences of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19,21, and 23 thereby leading to changes in the amino acid sequences of theencoded MOLX proteins, without altering the functional ability of saidMOLX proteins. For example, nucleotide substitutions leading to aminoacid substitutions at “non-essential” amino acid residues can be made inthe sequence of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and24. A “non-essential” amino acid residue is a residue that can bealtered from the wild-type sequences of the MOLX proteins withoutaltering their biological activity, whereas an “essential” amino acidresidue is required for such biological activity. For example, aminoacid residues that are conserved among the MOLX proteins of theinvention are predicted to be particularly non-amenable to alteration.Amino acids for which conservative substitutions can be made arewell-known within the art.

[0228] Another aspect of the invention pertains to nucleic acidmolecules encoding MOLX proteins that contain changes in amino acidresidues that are not essential for activity. Such MOLX proteins differin amino acid sequence from SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18,20, 22, and 24 yet retain biological activity. In one embodiment, theisolated nucleic acid molecule comprises a nucleotide sequence encodinga protein, wherein the protein comprises an amino acid sequence at leastabout 45% homologous to the amino acid sequences of SEQ ID NOS:2, 4, 6,8, 10, 12, 14, 16, 18, 20, 22, and 24. Preferably, the protein encodedby the nucleic acid molecule is at least about 60% homologous to SEQ IDNOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24; more preferably atleast about 70% homologous to SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18,20, 22, and 24; still more preferably at least about 80% homologous toSEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24; even morepreferably at least about 90% homologous to SEQ ID NOS:2, 4, 6, 8, 10,12, 14, 16, 18, 20, 22, and 24; and most preferably at least about 95%homologous to SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24.

[0229] An isolated nucleic acid molecule encoding an MOLX proteinhomologous to the protein of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18,20, 22, and 24 can be created by introducing one or more nucleotidesubstitutions, additions or deletions into the nucleotide sequence ofSEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23 such that oneor more amino acid substitutions, additions or deletions are introducedinto the encoded protein.

[0230] Mutations can be introduced into SEQ ID NOS:2, 4, 6, 8, 10, 12,14, 16, 18, 20, 22, and 24 by standard techniques, such as site-directedmutagenesis and PCR-mediated mutagenesis. Preferably, conservative aminoacid substitutions are made at one or more predicted, non-essentialamino acid residues. A “conservative amino acid substitution” is one inwhich the amino acid residue is replaced with an amino acid residuehaving a similar side chain. Families of amino acid residues havingsimilar side chains have been defined within the art. These familiesinclude amino acids with basic side chains (e.g., lysine, arginine,histidine), acidic side chains (e.g., aspartic acid, glutamic acid),uncharged polar side chains (e.g., glycine, asparagine, glutamine,serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g.,alanine, valine, leucine, isoleucine, proline, phenylalanine,methionine, tryptophan), beta-branched side chains (e.g., threonine,valine, isoleucine) and aromatic side chains (e.g., tyrosine,phenylalanine, tryptophan, histidine). Thus, a predicted non-essentialamino acid residue in the MOLX protein is replaced with another aminoacid residue from the same side chain family. Alternatively, in anotherembodiment, mutations can be introduced randomly along all or part of anMOLX coding sequence, such as by saturation mutagenesis, and theresultant mutants can be screened for MOLX biological activity toidentify mutants that retain activity. Following mutagenesis of SEQ IDNOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23, the encoded proteincan be expressed by any recombinant technology known in the art and theactivity of the protein can be determined.

[0231] The relatedness of amino acid families may also be determinedbased on side chain interactions. Substituted amino acids may be fullyconserved “strong” residues or fully conserved “weak” residues. The“strong” group of conserved amino acid residues may be any one of thefollowing groups: STA, NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW,wherein the single letter amino acid codes are grouped by those aminoacids that may be substituted for each other. Likewise, the “weak” groupof conserved residues may be any one of the following: CSA, ATV, SAG,STNK, STPA, SGND, SNDEQK, NDEQHK, NEQHRK, VLIM, HFY, wherein the letterswithin each group represent the single letter amino acid code.

[0232] In one embodiment, a mutant MOLX protein can be assayed for (i)the ability to form protein:protein interactions with other MOLXproteins, other cell-surface proteins, or biologically-active portionsthereof, (ii) complex formation between a mutant MOLX protein and anMOLX ligand; or (iii) the ability of a mutant MOLX protein to bind to anintracellular target protein or biologically-active portion thereof;(e.g. avidin proteins).

[0233] In yet another embodiment, a mutant MOLX protein can be assayedfor the ability to regulate a specific biological function (e.g.,regulation of insulin release).

[0234] Antisense Nucleic Acids

[0235] Another aspect of the invention pertains to isolated antisensenucleic acid molecules that are hybridizable to or complementary to thenucleic acid molecule comprising the nucleotide sequence of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23, or fragments, analogs orderivatives thereof. An “antisense” nucleic acid comprises a nucleotidesequence that is complementary to a “sense” nucleic acid encoding aprotein (e.g., complementary to the coding strand of a double-strandedcDNA molecule or complementary to an mRNA sequence). In specificaspects, antisense nucleic acid molecules are provided that comprise asequence complementary to at least about 10, 25, 50, 100, 250 or 500nucleotides or an entire MOLX coding strand, or to only a portionthereof. Nucleic acid molecules encoding fragments, homologs,derivatives and analogs of an MOLX protein of SEQ ID NOS:2, 4, 6, 8, 10,12, 14, 16, 18, 20, 22, and 24, or antisense nucleic acids complementaryto an MOLX nucleic acid sequence of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13,15, 17, 19, 21, and 23, are additionally provided.

[0236] In one embodiment, an antisense nucleic acid molecule isantisense to a “coding region” of the coding strand of a nucleotidesequence encoding an MOLX protein. The term “coding region” refers tothe region of the nucleotide sequence comprising codons which aretranslated into amino acid residues. In another embodiment, theantisense nucleic acid molecule is antisense to a “noncoding region” ofthe coding strand of a nucleotide sequence encoding the MOLX protein.The term “noncoding region” refers to 5′ and 3′ sequences which flankthe coding region that are not translated into amino acids (i.e., alsoreferred to as 5′ and 3′ untranslated regions).

[0237] Given the coding strand sequences encoding the MOLX proteindisclosed herein, antisense nucleic acids of the invention can bedesigned according to the rules of Watson and Crick or Hoogsteen basepairing. The antisense nucleic acid molecule can be complementary to theentire coding region of MOLX mRNA, but more preferably is anoligonucleotide that is antisense to only a portion of the coding ornoncoding region of MOLX mRNA. For example, the antisenseoligonucleotide can be complementary to the region surrounding thetranslation start site of MOLX mRNA. An antisense oligonucleotide canbe, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50nucleotides in length. An antisense nucleic acid of the invention can beconstructed using chemical synthesis or enzymatic ligation reactionsusing procedures known in the art. For example, an antisense nucleicacid (e.g., an antisense oligonucleotide) can be chemically synthesizedusing naturally-occurring nucleotides or variously modified nucleotidesdesigned to increase the biological stability of the molecules or toincrease the physical stability of the duplex formed between theantisense and sense nucleic acids (e.g., phosphorothioate derivativesand acridine substituted nucleotides can be used).

[0238] Examples of modified nucleotides that can be used to generate theantisense nucleic acid include: 5-fluorouracil, 5-bromouracil,5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine,5-(carboxyhydroxylmethyl) uracil,5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarboxymethyluracil, 5-methoxyuracil,2-methylthio-N-6-isopentenyladenine, uracil-5-oxyacetic acid (v),wybutoxosine, pseudouracil, queosine, 2-thiocytosine,5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v),5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3) w,and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can beproduced biologically using an expression vector into which a nucleicacid has been subcloned in an antisense orientation (i.e., RNAtranscribed from the inserted nucleic acid will be of an antisenseorientation to a target nucleic acid of interest, described further inthe following subsection).

[0239] The antisense nucleic acid molecules of the invention aretypically administered to a subject or generated in situ such that theyhybridize with or bind to cellular mRNA and/or genomic DNA encoding anMOLX protein to thereby inhibit expression of the protein (e.g., byinhibiting transcription and/or translation). The hybridization can beby conventional nucleotide complementarity to form a stable duplex, or,for example, in the case of an antisense nucleic acid molecule thatbinds to DNA duplexes, through specific interactions in the major grooveof the double helix. An example of a route of administration ofantisense nucleic acid molecules of the invention includes directinjection at a tissue site. Alternatively, antisense nucleic acidmolecules can be modified to target selected cells and then administeredsystemically. For example, for systemic administration, antisensemolecules can be modified such that they specifically bind to receptorsor antigens expressed on a selected cell surface (e.g., by linking theantisense nucleic acid molecules to peptides or antibodies that bind tocell surface receptors or antigens). The antisense nucleic acidmolecules can also be delivered to cells using the vectors describedherein. To achieve sufficient nucleic acid molecules, vector constructsin which the antisense nucleic acid molecule is placed under the controlof a strong pol II or pot III promoter are preferred.

[0240] In yet another embodiment, the antisense nucleic acid molecule ofthe invention is an α-anomeric nucleic acid molecule. An α-anomericnucleic acid molecule forms specific double-stranded hybrids withcomplementary RNA in which, contrary to the usual β-units, the strandsrun parallel to each other. See, e.g., Gaultier, et al., 1987. Nucl.Acids Res. 15: 6625-6641. The antisense nucleic acid molecule can alsocomprise a 2′-o-methylribonucleotide (see, e.g., Inoue, et al. 1987.Nucl. Acids Res. 15: 6131-6148) or a chimeric RNA-DNA analogue (see,e.g., Inoue, et al., 1987. FEBS Lett. 215: 327-330.

[0241] Ribozymes and PNA Moieties

[0242] Nucleic acid modifications include, by way of non-limitingexample, modified bases, and nucleic acids whose sugar phosphatebackbones are modified or derivatized. These modifications are carriedout at least in part to enhance the chemical stability of the modifiednucleic acid, such that they may be used, for example, as antisensebinding nucleic acids in therapeutic applications in a subject.

[0243] In one embodiment, an antisense nucleic acid of the invention isa ribozyme. Ribozymes are catalytic RNA molecules with ribonucleaseactivity that are capable of cleaving a single-stranded nucleic acid,such as an mRNA, to which they have a complementary region. Thus,ribozymes (e.g., hammerhead ribozymes as described in Haselhoff andGerlach 1988. Nature 334: 585-591) can be used to catalytically cleaveMOLX mRNA transcripts to thereby inhibit translation of MOLX mRNA. Aribozyme having specificity for an MOLX-encoding nucleic acid can bedesigned based upon the nucleotide sequence of an MOLX cDNA disclosedherein (i.e., SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and23). For example, a derivative of a Tetrahymena L-19 IVS RNA can beconstructed in which the nucleotide sequence of the active site iscomplementary to the nucleotide sequence to be cleaved in anMOLX-encoding mRNA. See, e.g., U.S. Pat. No. 4,987,071 to Cech, et al.and U.S. Pat. No. 5,116,742 to Cech, et al. MOLX mRNA can also be usedto select a catalytic RNA having a specific ribonuclease activity from apool of RNA molecules. See, e.g., Bartel et al., (1993) Science261:1411-1418.

[0244] Alternatively, MOLX gene expression can be inhibited by targetingnucleotide sequences complementary to the regulatory region of the MOLXnucleic acid (e.g., the MOLX promoter and/or enhancers) to form triplehelical structures that prevent transcription of the MOLX gene in targetcells. See, e.g., Helene, 1991. Anticancer Drug Des. 6: 569-84; Helene,et al. 1992. Ann. N.Y. Acad. Sci. 660: 27-36; Maher, 1992. Bioassays 14:807-15.

[0245] In various embodiments, the MOLX nucleic acids can be modified atthe base moiety, sugar moiety or phosphate backbone to improve, e.g.,the stability, hybridization, or solubility of the molecule. Forexample, the deoxyribose phosphate backbone of the nucleic acids can bemodified to generate peptide nucleic acids. See, e.g., Hyrup, et al.,1996. Bioorg Med Chem 4: 5-23. As used herein, the terms “peptidenucleic acids” or “PNAs” refer to nucleic acid mimics (e.g., DNA mimics)in which the deoxyribose phosphate backbone is replaced by apseudopeptide backbone and only the four natural nucleobases areretained. The neutral backbone of PNAs has been shown to allow forspecific hybridization to DNA and RNA under conditions of low ionicstrength. The synthesis of PNA oligomers can be performed using standardsolid phase peptide synthesis protocols as described in Hyrup, et al.,1996. supra; Perry-O'Keefe, et al., 1996. Proc. Natl. Acad. Sci. USA 93:14670-14675.

[0246] PNAs of MOLX can be used in therapeutic and diagnosticapplications. For example, PNAs can be used as antisense or antigeneagents for sequence-specific modulation of gene expression by, e.g.,inducing transcription or translation arrest or inhibiting replication.PNAs of MOLX can also be used, for example, in the analysis of singlebase pair mutations in a gene (e.g., PNA directed PCR clamping; asartificial restriction enzymes when used in combination with otherenzymes, e.g., S1 nucleases (see, Hyrup, et al., 1996.supra); or asprobes or primers for DNA sequence and hybridization (see, Hyrup, etal., 1996, supra; Perry-O'Keefe, et al., 1996. supra).

[0247] In another embodiment, PNAs of MOLX can be modified, e.g., toenhance their stability or cellular uptake, by attaching lipophilic orother helper groups to PNA, by the formation of PNA-DNA chimeras, or bythe use of liposomes or other techniques of drug delivery known in theart. For example, PNA-DNA chimeras of MOLX can be generated that maycombine the advantageous properties of PNA and DNA. Such chimeras allowDNA recognition enzymes (e.g., RNase H and DNA polymerases) to interactwith the DNA portion while the PNA portion would provide high bindingaffinity and specificity. PNA-DNA chimeras can be linked using linkersof appropriate lengths selected in terms of base stacking, number ofbonds between the nucleobases, and orientation (see, Hyrup, et al.,1996. supra). The synthesis of PNA-DNA chimeras can be performed asdescribed in Hyrup, et al., 1996. supra and Finn, et al., 1996. NuclAcids Res 24: 3357-3363. For example, a DNA chain can be synthesized ona solid support using standard phosphoramidite coupling chemistry, andmodified nucleoside analogs, e.g.,5′-(4-methoxytrityl)amino-5′-deoxy-thymidine phosphoramidite, can beused between the PNA and the 5′ end of DNA. See, e.g., Mag, et al.,1989. Nucl Acid Res 17: 5973-5988. PNA monomers are then coupled in astepwise manner to produce a chimeric molecule with a 5′ PNA segment anda 3′ DNA segment. See, e.g., Finn, et al., 1996. supra. Alternatively,chimeric molecules can be synthesized with a 5′ DNA segment and a 3′ PNAsegment. See, e.g., Petersen, et al., 1975. Bioorg. Med. Chem. Lett. 5:1119-11124.

[0248] In other embodiments, the oligonucleotide may include otherappended groups such as peptides (e.g., for targeting host cellreceptors in vivo), or agents facilitating transport across the cellmembrane (see, e.g., Letsinger, et al., 1989. Proc. Natl. Acad. Sci.U.S.A. 86: 6553-6556; Lemaitre, et al., 1987. Proc. Natl. Acad. Sci. 84:648-652; PCT Publication No. WO88/09810) or the blood-brain barrier(see, e.g., PCT Publication No. WO 89/10134). In addition,oligonucleotides can be modified with hybridization triggered cleavageagents (see, e.g., Krol, et al., 1988. BioTechniques 6:958-976) orintercalating agents (see, e.g., Zon, 1988. Pharm. Res. 5: 539-549). Tothis end, the oligonucleotide may be conjugated to another molecule,e.g., a peptide, a hybridization triggered cross-linking agent, atransport agent, a hybridization-triggered cleavage agent, and the like.

[0249] MOLX Polypeptides

[0250] A polypeptide according to the invention includes a polypeptideincluding the amino acid sequence of MOLX polypeptides whose sequencesare provided in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and24. The invention also includes a mutant or variant protein any of whoseresidues may be changed from the corresponding residues shown in SEQ IDNOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 while still encodinga protein that maintains its MOLX activities and physiologicalfunctions, or a functional fragment thereof.

[0251] In general, an MOLX variant that preserves MOLX-like functionincludes any variant in which residues at a particular position in thesequence have been substituted by other amino acids, and further includethe possibility of inserting an additional residue or residues betweentwo residues of the parent protein as well as the possibility ofdeleting one or more residues from the parent sequence. Any amino acidsubstitution, insertion, or deletion is encompassed by the invention. Infavorable circumstances, the substitution is a conservative substitutionas defined above.

[0252] One aspect of the invention pertains to isolated MOLX proteins,and biologically-active portions thereof, or derivatives, fragments,analogs or homologs thereof. Also provided are polypeptide fragmentssuitable for use as immunogens to raise anti-MOLX antibodies. In oneembodiment, native MOLX proteins can be isolated from cells or tissuesources by an appropriate purification scheme using standard proteinpurification techniques. In another embodiment, MOLX proteins areproduced by recombinant DNA techniques. Alternative to recombinantexpression, an MOLX protein or polypeptide can be synthesized chemicallyusing standard peptide synthesis techniques.

[0253] An “isolated” or “purified” polypeptide or protein orbiologically-active portion thereof is substantially free of cellularmaterial or other contaminating proteins from the cell or tissue sourcefrom which the MOLX protein is derived, or substantially free fromchemical precursors or other chemicals when chemically synthesized. Thelanguage “substantially free of cellular material” includes preparationsof MOLX proteins in which the protein is separated from cellularcomponents of the cells from which it is isolated orrecombinantly-produced. In one embodiment, the language “substantiallyfree of cellular material” includes preparations of MOLX proteins havingless than about 30% (by dry weight) of non-MOLX proteins (also referredto herein as a “contaminating protein”), more preferably less than about20% of non-MOLX proteins, still more preferably less than about 10% ofnon-MOLX proteins, and most preferably less than about 5% of non-MOLXproteins. When the MOLX protein or biologically-active portion thereofis recombinantly-produced, it is also preferably substantially free ofculture medium, i.e., culture medium represents less than about 20%,more preferably less than about 10%, and most preferably less than about5% of the volume of the MOLX protein preparation.

[0254] The language “substantially free of chemical precursors or otherchemicals” includes preparations of MOLX proteins in which the proteinis separated from chemical precursors or other chemicals that areinvolved in the synthesis of the protein. In one embodiment, thelanguage “substantially free of chemical precursors or other chemicals”includes preparations of MOLX proteins having less than about 30% (bydry weight) of chemical precursors or non-MOLX chemicals, morepreferably less than about 20% chemical precursors or non-MOLXchemicals, still more preferably less than about 10% chemical precursorsor non-MOLX chemicals, and most preferably less than about 5% chemicalprecursors or non-MOLX chemicals.

[0255] Biologically-active portions of MOLX proteins include peptidescomprising amino acid sequences sufficiently homologous to or derivedfrom the amino acid sequences of the MOLX proteins (e.g., the amino acidsequence shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and24) that include fewer amino acids than the full-length MOLX proteins,and exhibit at least one activity of an MOLX protein. Typically,biologically-active portions comprise a domain or motif with at leastone activity of the MOLX protein. A biologically-active portion of anMOLX protein can be a polypeptide which is, for example, 10, 25, 50, 100or more amino acid residues in length.

[0256] Moreover, other biologically-active portions, in which otherregions of the protein are deleted, can be prepared by recombinanttechniques and evaluated for one or more of the functional activities ofa native MOLX protein.

[0257] In an embodiment, the MOLX protein has an amino acid sequenceshown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. Inother embodiments, the MOLX protein is substantially homologous to SEQID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24, and retains thefunctional activity of the protein of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14,16, 18, 20, 22, and 24, yet differs in amino acid sequence due tonatural allelic variation or mutagenesis, as described in detail, below.Accordingly, in another embodiment, the MOLX protein is a protein thatcomprises an amino acid sequence at least about 45% homologous to theamino acid sequence SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22,and 24, and retains the functional activity of the MOLX proteins of SEQID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24.

[0258] Determining Homology Between Two or More Sequences

[0259] To determine the percent homology of two amino acid sequences orof two nucleic acids, the sequences are aligned for optimal comparisonpurposes (e.g., gaps can be introduced in the sequence of a first aminoacid or nucleic acid sequence for optimal alignment with a second aminoor nucleic acid sequence). The amino acid residues or nucleotides atcorresponding amino acid positions or nucleotide positions are thencompared. When a position in the first sequence is occupied by the sameamino acid residue or nucleotide as the corresponding position in thesecond sequence, then the molecules are homologous at that position(i.e., as used herein amino acid or nucleic acid “homology” isequivalent to amino acid or nucleic acid “identity”).

[0260] The nucleic acid sequence homology may be determined as thedegree of identity between two sequences. The homology may be determinedusing computer programs known in the art, such as GAP software providedin the GCG program package. See, Needleman and Wunsch, 1970. J Mol Biol48: 443-453. Using GCG GAP software with the following settings fornucleic acid sequence comparison: GAP creation penalty of 5.0 and GAPextension penalty of 0.3, the coding region of the analogous nucleicacid sequences referred to above exhibits a degree of identitypreferably of at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%, withthe CDS (encoding) part of the DNA sequence shown in SEQ ID NOS: 1, 3,5, 7, 9, 11, 13, 15, 17, 19, 21, and 23.

[0261] The term “sequence identity” refers to the degree to which twopolynucleotide or polypeptide sequences are identical on aresidue-by-residue basis over a particular region of comparison. Theterm “percentage of sequence identity” is calculated by comparing twooptimally aligned sequences over that region of comparison, determiningthe number of positions at which the identical nucleic acid base (e.g.,A, T, C, G, U, or I, in the case of nucleic acids) occurs in bothsequences to yield the number of matched positions, dividing the numberof matched positions by the total number of positions in the region ofcomparison (i.e., the window size), and multiplying the result by 100 toyield the percentage of sequence identity. The term “substantialidentity” as used herein denotes a characteristic of a polynucleotidesequence, wherein the polynucleotide comprises a sequence that has atleast 80 percent sequence identity, preferably at least 85 percentidentity and often 90 to 95 percent sequence identity, more usually atleast 99 percent sequence identity as compared to a reference sequenceover a comparison region.

[0262] Chimeric and Fusion Proteins

[0263] The invention also provides MOLX chimeric or fusion proteins. Asused herein, an MOLX “chimeric protein” or “fusion protein” comprises anMOLX polypeptide operatively-linked to a non-MOLX polypeptide. An “MOLXpolypeptide” refers to a polypeptide having an amino acid sequencecorresponding to an MOLX protein (SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16,18, 20, 22, and 24), whereas a “non-MOLX polypeptide” refers to apolypeptide having an amino acid sequence corresponding to a proteinthat is not substantially homologous to the MOLX protein, e.g., aprotein that is different from the MOLX protein and that is derived fromthe same or a different organism. Within an MOLX fusion protein the MOLXpolypeptide can correspond to all or a portion of an MOLX protein. Inone embodiment, an MOLX fusion protein comprises at least onebiologically-active portion of an MOLX protein. In another embodiment,an MOLX fusion protein comprises at least two biologically-activeportions of an MOLX protein. In yet another embodiment, an MOLX fusionprotein comprises at least three biologically-active portions of an MOLXprotein. Within the fusion protein, the term “operatively-linked” isintended to indicate that the MOLX polypeptide and the non-MOLXpolypeptide are fused in-frame with one another. The non-MOLXpolypeptide can be fused to the N-terminus or C-terminus of the MOLXpolypeptide.

[0264] In one embodiment, the fusion protein is a GST-MOLX fusionprotein in which the MOLX sequences are fused to the C-terminus of theGST (glutathione S-transferase) sequences. Such fusion proteins canfacilitate the purification of recombinant MOLX polypeptides.

[0265] In another embodiment, the fusion protein is an MOLX proteincontaining a heterologous signal sequence at its N-terminus. In certainhost cells (e.g., mammalian host cells), expression and/or secretion ofMOLX can be increased through use of a heterologous signal sequence.

[0266] In yet another embodiment, the fusion protein is anMOLX-immunoglobulin fusion protein in which the MOLX sequences are fusedto sequences derived from a member of the immunoglobulin protein family.The MOLX-immunoglobulin fusion proteins of the invention can beincorporated into pharmaceutical compositions and administered to asubject to inhibit an interaction between an MOLX ligand and an MOLXprotein on the surface of a cell, to thereby suppress MOLX-mediatedsignal transduction in vivo. The MOLX-immunoglobulin fusion proteins canbe used to affect the bioavailability of an MOLX cognate ligand.Inhibition of the MOLX ligand/MOLX interaction may be usefultherapeutically for both the treatment of proliferative anddifferentiative disorders, as well as modulating (e.g. promoting orinhibiting) cell survival. Moreover, the MOLX-immunoglobulin fusionproteins of the invention can be used as immunogens to produce anti-MOLXantibodies in a subject, to purify MOLX ligands, and in screening assaysto identify molecules that inhibit the interaction of MOLX with an MOLXligand.

[0267] An MOLX chimeric or fusion protein of the invention can beproduced by standard recombinant DNA techniques. For example, DNAfragments coding for the different polypeptide sequences are ligatedtogether in-frame in accordance with conventional techniques, e.g., byemploying blunt-ended or stagger-ended termini for ligation, restrictionenzyme digestion to provide for appropriate termini, filling-in ofcohesive ends as appropriate, alkaline phosphatase treatment to avoidundesirable joining, and enzymatic ligation. In another embodiment, thefusion gene can be synthesized by conventional techniques includingautomated DNA synthesizers. Alternatively, PCR amplification of genefragments can be carried out using anchor primers that give rise tocomplementary overhangs between two consecutive gene fragments that cansubsequently be annealed and reamplified to generate a chimeric genesequence (see, e.g., Ausubel, et al. (eds.) CURRENT PROTOCOLS INMOLECULAR BIOLOGY, John Wiley & Sons, 1992). Moreover, many expressionvectors are commercially available that already encode a fusion moiety(e.g., a GST polypeptide). An MOLX-encoding nucleic acid can be clonedinto such an expression vector such that the fusion moiety is linkedin-frame to the MOLX protein.

[0268] MOLX Agonists and Antagonists

[0269] The invention also pertains to variants of the MOLX proteins thatfunction as either MOLX agonists (i.e., mimetics) or as MOLXantagonists. Variants of the MOLX protein can be generated bymutagenesis (e.g., discrete point mutation or truncation of the MOLXprotein). An agonist of the MOLX protein can retain substantially thesame, or a subset of, the biological activities of the naturallyoccurring form of the MOLX protein. An antagonist of the MOLX proteincan inhibit one or more of the activities of the naturally occurringform of the MOLX protein by, for example, competitively binding to adownstream or upstream member of a cellular signaling cascade whichincludes the MOLX protein. Thus, specific biological effects can beelicited by treatment with a variant of limited function. In oneembodiment, treatment of a subject with a variant having a subset of thebiological activities of the naturally occurring form of the protein hasfewer side effects in a subject relative to treatment with the naturallyoccurring form of the MOLX proteins.

[0270] Variants of the MOLX proteins that function as either MOLXagonists (i.e., mimetics) or as MOLX antagonists can be identified byscreening combinatorial libraries of mutants (e.g., truncation mutants)of the MOLX proteins for MOLX protein agonist or antagonist activity. Inone embodiment, a variegated library of MOLX variants is generated bycombinatorial mutagenesis at the nucleic acid level and is encoded by avariegated gene library. A variegated library of MOLX variants can beproduced by, for example, enzymatically ligating a mixture of syntheticoligonucleotides into gene sequences such that a degenerate set ofpotential MOLX sequences is expressible as individual polypeptides, oralternatively, as a set of larger fusion proteins (e.g., for phagedisplay) containing the set of MOLX sequences therein. There are avariety of methods which can be used to produce libraries of potentialMOLX variants from a degenerate oligonucleotide sequence. Chemicalsynthesis of a degenerate gene sequence can be performed in an automaticDNA synthesizer, and the synthetic gene then ligated into an appropriateexpression vector. Use of a degenerate set of genes allows for theprovision, in one mixture, of all of the sequences encoding the desiredset of potential MOLX sequences. Methods for synthesizing degenerateoligonucleotides are well-known within the art. See, e.g., Narang, 1983.Tetrahedron 39: 3; Itakura, et al., 1984. Annu. Rev. Biochem. 53: 323;Itakura, et al., 1984. Science 198: 1056; Ike, et al., 1983. Nucl. AcidsRes. 11: 477.

[0271] Polypeptide Libraries

[0272] In addition, libraries of fragments of the MOLX protein codingsequences can be used to generate a variegated population of MOLXfragments for screening and subsequent selection of variants of an MOLXprotein. In one embodiment, a library of coding sequence fragments canbe generated by treating a double stranded PCR fragment of an MOLXcoding sequence with a nuclease under conditions wherein nicking occursonly about once per molecule, denaturing the double stranded DNA,renaturing the DNA to form double-stranded DNA that can includesense/antisense pairs from different nicked products, removing singlestranded portions from reformed duplexes by treatment with S1 nuclease,and ligating the resulting fragment library into an expression vector.By this method, expression libraries can be derived which encodesN-terminal and internal fragments of various sizes of the MOLX proteins.

[0273] Various techniques are known in the art for screening geneproducts of combinatorial libraries made by point mutations ortruncation, and for screening cDNA libraries for gene products having aselected property. Such techniques are adaptable for rapid screening ofthe gene libraries generated by the combinatorial mutagenesis of MOLXproteins. The most widely used techniques, which are amenable to highthroughput analysis, for screening large gene libraries typicallyinclude cloning the gene library into replicable expression vectors,transforming appropriate cells with the resulting library of vectors,and expressing the combinatorial genes under conditions in whichdetection of a desired activity facilitates isolation of the vectorencoding the gene whose product was detected. Recursive ensemblemutagenesis (REM), a new technique that enhances the frequency offunctional mutants in the libraries, can be used in combination with thescreening assays to identify MOLX variants. See, e.g., Arkin andYourvan, 1992. Proc. Natl. Acad. Sci. USA 89: 7811-7815; Delgrave, etal., 1993. Protein Engineering 6:327-331.

[0274] Anti-MOLX Antibodies

[0275] The invention encompasses antibodies and antibody fragments, suchas F_(ab) or (F_(ab))₂, that bind immunospecifically to any of the MOLXpolypeptides of said invention.

[0276] An isolated MOLX protein, or a portion or fragment thereof, canbe used as an immunogen to generate antibodies that bind to MOLXpolypeptides using standard techniques for polyclonal and monoclonalantibody preparation. The full-length MOLX proteins can be used or,alternatively, the invention provides antigenic peptide fragments ofMOLX proteins for use as immunogens. The antigenic MOLX peptidescomprises at least 4 amino acid residues of the amino acid sequenceshown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 andencompasses an epitope of MOLX such that an antibody raised against thepeptide forms a specific immune complex with MOLX. Preferably, theantigenic peptide comprises at least 6, 8, 10, 15, 20, or 30 amino acidresidues. Longer antigenic peptides are sometimes preferable overshorter antigenic peptides, depending on use and according to methodswell known to someone skilled in the art.

[0277] In certain embodiments of the invention, at least one epitopeencompassed by the antigenic peptide is a region of MOLX that is locatedon the surface of the protein (e.g., a hydrophilic region). As a meansfor targeting antibody production, hydropathy plots showing regions ofhydrophilicity and hydrophobicity may be generated by any method wellknown in the art, including, for example, the Kyte Doolittle or the HoppWoods methods, either with or without Fourier transformation (see, e.g.,Hopp and Woods, 1981. Proc. Nat. Acad. Sci. USA 78: 3824-3828; Kyte andDoolittle, 1982. J. Mol. Biol. 157: 105-142, each incorporated herein byreference in their entirety).

[0278] As disclosed herein, MOLX protein sequences of SEQ ID NOS:2, 4,6, 8, 10, 12, 14, 16, 18, 20, 22, and 24, or derivatives, fragments,analogs or homologs thereof, may be utilized as immunogens in thegeneration of antibodies that immunospecifically-bind these proteincomponents. The term “antibody” as used herein refers to immunoglobulinmolecules and immunologically-active portions of immunoglobulinmolecules, i.e., molecules that contain an antigen binding site thatspecifically-binds (immunoreacts with) an antigen, such as MOLX. Suchantibodies include, but are not limited to, polyclonal, monoclonal,chimeric, single chain, F_(ab) and F_((ab′)2) fragments, and an F_(ab)expression library. In a specific embodiment, antibodies to human MOLXproteins are disclosed. Various procedures known within the art may beused for the production of polyclonal or monoclonal antibodies to anMOLX protein sequence of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20,22, and 24, or a derivative, fragment, analog or homolog thereof. Someof these proteins are discussed below.

[0279] For the production of polyclonal antibodies, various suitablehost animals (e.g., rabbit, goat, mouse or other mammal) may beimmunized by injection with the native protein, or a synthetic variantthereof, or a derivative of the foregoing. An appropriate immunogenicpreparation can contain, for example, recombinantly-expressed MOLXprotein or a chemically-synthesized MOLX polypeptide. The preparationcan further include an adjuvant. Various adjuvants used to increase theimmunological response include, but are not limited to, Freund's(complete and incomplete), mineral gels (e.g., aluminum hydroxide),surface active substances (e.g., lysolecithin, pluronic polyols,polyanions, peptides, oil emulsions, dinitrophenol, etc.), humanadjuvants such as Bacille Calmette-Guerin and Corynebacterium parvum, orsimilar immunostimulatory agents. If desired, the antibody moleculesdirected against MOLX can be isolated from the mammal (e.g., from theblood) and further purified by well known techniques, such as protein Achromatography to obtain the IgG fraction.

[0280] The term “monoclonal antibody” or “monoclonal antibodycomposition”, as used herein, refers to a population of antibodymolecules that contain only one species of an antigen binding sitecapable of immunoreacting with a particular epitope of MOLX. Amonoclonal antibody composition thus typically displays a single bindingaffinity for a particular MOLX protein with which it immunoreacts. Forpreparation of monoclonal antibodies directed towards a particular MOLXprotein, or derivatives, fragments, analogs or homologs thereof, anytechnique that provides for the production of antibody molecules bycontinuous cell line culture may be utilized. Such techniques include,but are not limited to, the hybridoma technique (see, e.g., Kohler &Milstein, 1975. Nature 256: 495-497); the trioma technique; the humanB-cell hybridoma technique (see, e.g., Kozbor, et al., 1983. Immunol.Today 4: 72) and the EBV hybridoma technique to produce human monoclonalantibodies (see, e.g., Cole, et al., 1985. In: MONOCLONAL ANTIBODIES ANDCANCER THERAPY, Alan R. Liss, Inc., pp. 77-96). Human monoclonalantibodies may be utilized in the practice of the invention and may beproduced by using human hybridomas (see, e.g., Cote, et al., 1983. ProcNatl Acad Sci USA 80: 2026-2030) or by transforming human B-cells withEpstein Barr Virus in vitro (see, e.g., Cole, et al., 1985. In:MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp.77-96). Each of the above citations is incorporated herein by referencein their entirety.

[0281] According to the invention, techniques can be adapted for theproduction of single-chain antibodies specific to an MOLX protein (see,e.g., U.S. Pat. No. 4,946,778). In addition, methods can be adapted forthe construction of F_(ab) expression libraries (see, e.g., Huse, etal., 1989. Science 246: 1275-1281) to allow rapid and effectiveidentification of monoclonal F_(ab) fragments with the desiredspecificity for an MOLX protein or derivatives, fragments, analogs orhomologs thereof. Non-human antibodies can be “humanized” by techniqueswell known in the art. See, e.g., U.S. Pat. No. 5,225,539. Antibodyfragments that contain the idiotypes to an MOLX protein may be producedby techniques known in the art including, but not limited to: (i) anF_((ab)2) fragment produced by pepsin digestion of an antibody molecule;(ii) an F_(ab) fragment generated by reducing the disulfide bridges ofan F_((ab)2) fragment; (iii) an F_(ab) fragment generated by thetreatment of the antibody molecule with papain and a reducing agent; and(iv) F_(v) fragments.

[0282] Additionally, recombinant anti-MOLX antibodies, such as chimericand humanized monoclonal antibodies, comprising both human and non-humanportions, which can be made using standard recombinant DNA techniques,are within the scope of the invention. Such chimeric and humanizedmonoclonal antibodies can be produced by recombinant DNA techniquesknown in the art, for example using methods described in InternationalApplication No. PCT/US86/02269; European Patent Application No. 184,187;European Patent Application No. 171,496; European Patent Application No.173,494; PCT International Publication No. WO 86/01533; U.S. Pat. No.4,816,567; U.S. Pat. No. 5,225,539; European Patent Application No.125,023; Better, et al., 1988. Science 240: 1041-1043; Liu, et al.,1987. Proc. Natl. Acad. Sci. USA 84: 3439-3443; Liu, et al., 1987. J.Immunol. 139: 3521-3526; Sun, et al., 1987. Proc. Natl. Acad. Sci. USA84: 214-218; Nishimura, et al., 1987. Cancer Res. 47: 999-1005; Wood, etal., 1985. Nature 314:446449; Shaw, et al., 1988. J. Natl. Cancer Inst.80: 1553-1559); Morrison (1985) Science 229:1202-1207; Oi, et al. (1986)BioTechniques 4:214; Jones, et al., 1986. Nature 321: 552-525;Verhoeyan, et al., 1988. Science 239: 1534; and Beidler, et al., 1988.J. Immunol. 141: 4053-4060. Each of the above citations are incorporatedherein by reference in their entirety.

[0283] In one embodiment, methods for the screening of antibodies thatpossess the desired specificity include, but are not limited to,enzyme-linked immunosorbent assay (ELISA) and otherimmunologically-mediated techniques known within the art. In a specificembodiment, selection of antibodies that are specific to a particulardomain of an MOLX protein is facilitated by generation of hybridomasthat bind to the fragment of an MOLX protein possessing such a domain.Thus, antibodies that are specific for a desired domain within an MOLXprotein, or derivatives, fragments, analogs or homologs thereof, arealso provided herein.

[0284] Anti-MOLX antibodies may be used in methods known within the artrelating to the localization and/or quantitation of an MOLX protein(e.g., for use in measuring levels of the MOLX protein withinappropriate physiological samples, for use in diagnostic methods, foruse in imaging the protein, and the like). In a given embodiment,antibodies for MOLX proteins, or derivatives, fragments, analogs orhomologs thereof, that contain the antibody derived binding domain, areutilized as pharmacologically-active compounds (hereinafter“Therapeutics”).

[0285] An anti-MOLX antibody (e.g., monoclonal antibody) can be used toisolate an MOLX polypeptide by standard techniques, such as affinitychromatography or immunoprecipitation. An anti-MOLX antibody canfacilitate the purification of natural MOLX polypeptide from cells andof recombinantly-produced MOLX polypeptide expressed in host cells.Moreover, an anti-MOLX antibody can be used to detect MOLX protein(e.g., in a cellular lysate or cell supernatant) in order to evaluatethe abundance and pattern of expression of the MOLX protein. Anti-MOLXantibodies can be used diagnostically to monitor protein levels intissue as part of a clinical testing procedure, e.g., to, for example,determine the efficacy of a given treatment regimen. Detection can befacilitated by coupling (i.e., physically linking) the antibody to adetectable substance. Examples of detectable substances include variousenzymes, prosthetic groups, fluorescent materials, luminescentmaterials, bioluminescent materials, and radioactive materials. Examplesof suitable enzymes include horseradish peroxidase, alkalinephosphatase, β-galactosidase, or acetylcholinesterase; examples ofsuitable prosthetic group complexes include streptavidin/biotin andavidintbiotin; examples of suitable fluorescent materials includeumbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine,dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; anexample of a luminescent material includes luminol; examples ofbioluminescent materials include luciferase, luciferin, and aequorin,and examples of suitable radioactive material include ¹²⁵I, ¹³¹I, ³⁵S or³H.

[0286] MOLX Recombinant Expression Vectors and Host Cells

[0287] Another aspect of the invention pertains to vectors, preferablyexpression vectors, containing a nucleic acid encoding an MOLX protein,or derivatives, fragments, analogs or homologs thereof. As used herein,the term “vector” refers to a nucleic acid molecule capable oftransporting another nucleic acid to which it has been linked. One typeof vector is a “plasmid”, which refers to a circular double stranded DNAloop into which additional DNA segments can be ligated. Another type ofvector is a viral vector, wherein additional DNA segments can be ligatedinto the viral genome. Certain vectors are capable of autonomousreplication in a host cell into which they are introduced (e.g.,bacterial vectors having a bacterial origin of replication and episomalmammalian vectors). Other vectors (e.g., non-episomal mammalian vectors)are integrated into the genome of a host cell upon introduction into thehost cell, and thereby are replicated along with the host genome.Moreover, certain vectors are capable of directing the expression ofgenes to which they are operatively-linked. Such vectors are referred toherein as “expression vectors”. In general, expression vectors ofutility in recombinant DNA techniques are often in the form of plasmids.In the present specification, “plasmid” and “vector” can be usedinterchangeably as the plasmid is the most commonly used form of vector.However, the invention is intended to include such other forms ofexpression vectors, such as viral vectors (e.g., replication defectiveretroviruses, adenoviruses and adeno-associated viruses), which serveequivalent functions.

[0288] The recombinant expression vectors of the invention comprise anucleic acid of the invention in a form suitable for expression of thenucleic acid in a host cell, which means that the recombinant expressionvectors include one or more regulatory sequences, selected on the basisof the host cells to be used for expression, that is operatively-linkedto the nucleic acid sequence to be expressed. Within a recombinantexpression vector, “operably-linked” is intended to mean that thenucleotide sequence of interest is linked to the regulatory sequence(s)in a manner that allows for expression of the nucleotide sequence (e.g.,in an in vitro transcription/translation system or in a host cell whenthe vector is introduced into the host cell).

[0289] The term “regulatory sequence” is intended to includes promoters,enhancers and other expression control elements (e.g., polyadenylationsignals). Such regulatory sequences are described, for example, inGoeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, AcademicPress, San Diego, Calif. (1990). Regulatory sequences include those thatdirect constitutive expression of a nucleotide sequence in many types ofhost cell and those that direct expression of the nucleotide sequenceonly in certain host cells (e.g., tissue-specific regulatory sequences).It will be appreciated by those skilled in the art that the design ofthe expression vector can depend on such factors as the choice of thehost cell to be transformed, the level of expression of protein desired,etc. The expression vectors of the invention can be introduced into hostcells to thereby produce proteins or peptides, including fusion proteinsor peptides, encoded by nucleic acids as described herein (e.g., MOLXproteins, mutant forms of MOLX proteins, fusion proteins, etc.).

[0290] The recombinant expression vectors of the invention can bedesigned for expression of MOLX proteins in prokaryotic or eukaryoticcells. For example, MOLX proteins can be expressed in bacterial cellssuch as Escherichia coli, insect cells (using baculovirus expressionvectors) yeast cells or mammalian cells. Suitable host cells arediscussed further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS INENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Alternatively,the recombinant expression vector can be transcribed and translated invitro, for example using T7 promoter regulatory sequences and T7polymerase.

[0291] Expression of proteins in prokaryotes is most often carried outin Escherichia coli with vectors containing constitutive or induciblepromoters directing the expression of either fusion or non-fusionproteins. Fusion vectors add a number of amino acids to a proteinencoded therein, usually to the amino terminus of the recombinantprotein. Such fusion vectors typically serve three purposes: (i) toincrease expression of recombinant protein; (ii) to increase thesolubility of the recombinant protein; and (iii) to aid in thepurification of the recombinant protein by acting as a ligand inaffinity purification. Often, in fusion expression vectors, aproteolytic cleavage site is introduced at the junction of the fusionmoiety and the recombinant protein to enable separation of therecombinant protein from the fusion moiety subsequent to purification ofthe fusion protein. Such enzymes, and their cognate recognitionsequences, include Factor Xa, thrombin and enterokinase. Typical fusionexpression vectors include pGEX (Pharmacia Biotech Inc; Smith andJohnson, 1988. Gene 67: 31-40), pMAL (New England Biolabs, Beverly,Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) that fuse glutathioneS-transferase (GST), maltose E binding protein, or protein A,respectively, to the target recombinant protein.

[0292] Examples of suitable inducible non-fusion E. coli expressionvectors include pTrc (Amrann et al., (1988) Gene 69:301-315) and pET 11d(Studier et al., GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185,Academic Press, San Diego, Calif. (1990) 60-89).

[0293] One strategy to maximize recombinant protein expression in E.coli is to express the protein in a host bacteria with an impairedcapacity to proteolytically cleave the recombinant protein. See, e.g.,Gottesman, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185,Academic Press, San Diego, Calif. (1990) 119-128. Another strategy is toalter the nucleic acid sequence of the nucleic acid to be inserted intoan expression vector so that the individual codons for each amino acidare those preferentially utilized in E. coli (see, e.g., Wada, et al.,1992. Nucl. Acids Res. 20: 2111-2118). Such alteration of nucleic acidsequences of the invention can be carried out by standard DNA synthesistechniques.

[0294] In another embodiment, the MOLX expression vector is a yeastexpression vector. Examples of vectors for expression in yeastSaccharomyces cerivisae include pYepSec I (Baldari, et al., 1987. EMBOJ. 6: 229-234), pMFa (Kurjan and Herskowitz, 1982. Cell 30: 933-943),pJRY88 (Schultz et al., 1987. Gene 54: 113-123), pYES2 (InvitrogenCorporation, San Diego, Calif.), and picZ (InVitrogen Corp, San Diego,Calif.).

[0295] Alternatively, MOLX can be expressed in insect cells usingbaculovirus expression vectors. Baculovirus vectors available forexpression of proteins in cultured insect cells (e.g., SF9 cells)include the pAc series (Smith, et al., 1983. Mol. Cell. Biol. 3:2156-2165) and the pVL series (Lucklow and Summers, 1989. Virology 170:31-39).

[0296] In yet another embodiment, a nucleic acid of the invention isexpressed in mammalian cells using a mammalian expression vector.Examples of mammalian expression vectors include pCDM8 (Seed, 1987.Nature 329: 840) and pMT2PC (Kaufman, et al., 1987. EMBO J. 6: 187-195).When used in mammalian cells, the expression vector's control functionsare often provided by viral regulatory elements. For example, commonlyused promoters are derived from polyoma, adenovirus 2, cytomegalovirus,and simian virus 40. For other suitable expression systems for bothprokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 ofSambrook, et al., MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., ColdSpring Harbor Laboratory, Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y., 1989.

[0297] In another embodiment, the recombinant mammalian expressionvector is capable of directing expression of the nucleic acidpreferentially in a particular cell type (e.g., tissue-specificregulatory elements are used to express the nucleic acid).Tissue-specific regulatory elements are known in the art. Non-limitingexamples of suitable tissue-specific promoters include the albuminpromoter (liver-specific; Pinkert, et al., 1987. Genes Dev. 1: 268-277),lymphoid-specific promoters (Calame and Eaton, 1988. Adv. Immunol. 43:235-275), in particular promoters of T cell receptors (Winoto andBaltimore, 1989. EMBO J. 8: 729-733) and immunoglobulins (Banerji, etal., 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Cell 33:741-748), neuron-specific promoters (e.g., the neurofilament promoter;Byrne and Ruddle, 1989. Proc. Natl. Acad. Sci. USA 86: 5473-5477),pancreas-specific promoters (Edlund, et al., 1985. Science 230:912-916), and mammary gland-specific promoters (e.g., milk wheypromoter; U.S. Pat. No. 4,873,316 and European Application PublicationNo. 264,166). Developmentally-regulated promoters are also encompassed,e.g., the murine hox promoters (Kessel and Gruss, 1990. Science 249:374-379) and the ct-fetoprotein promoter (Campes and Tilghman, 1989.Genes Dev. 3: 537-546).

[0298] The invention further provides a recombinant expression vectorcomprising a DNA molecule of the invention cloned into the expressionvector in an antisense orientation. That is, the DNA molecule isoperatively-linked to a regulatory sequence in a manner that allows forexpression (by transcription of the DNA molecule) of an RNA moleculethat is antisense to MOLX mRNA. Regulatory sequences operatively linkedto a nucleic acid cloned in the antisense orientation can be chosen thatdirect the continuous expression of the antisense RNA molecule in avariety of cell types, for instance viral promoters and/or enhancers, orregulatory sequences can be chosen that direct constitutive, tissuespecific or cell type specific expression of antisense RNA. Theantisense expression vector can be in the form of a recombinant plasmid,phagemid or attenuated virus in which antisense nucleic acids areproduced under the control of a high efficiency regulatory region, theactivity of which can be determined by the cell type into which thevector is introduced. For a discussion of the regulation of geneexpression using antisense genes see, e.g., Weintraub, et al.,“Antisense RNA as a molecular tool for genetic analysis,” Reviews-Trendsin Genetics, Vol. 1(1) 1986.

[0299] Another aspect of the invention pertains to host cells into whicha recombinant expression vector of the invention has been introduced.The terms “host cell” and “recombinant host cell” are usedinterchangeably herein. It is understood that such terms refer not onlyto the particular subject cell but also to the progeny or potentialprogeny of such a cell. Because certain modifications may occur insucceeding generations due to either mutation or environmentalinfluences, such progeny may not, in fact, be identical to the parentcell, but are still included within the scope of the term as usedherein.

[0300] A host cell can be any prokaryotic or eukaryotic cell. Forexample, MOLX protein can be expressed in bacterial cells such as E.coli, insect cells, yeast or mammalian cells (such as Chinese hamsterovary cells (CHO) or COS cells). Other suitable host cells are known tothose skilled in the art.

[0301] Vector DNA can be introduced into prokaryotic or eukaryotic cellsvia conventional transformation or transfection techniques. As usedherein, the terms “transformation” and “transfection” are intended torefer to a variety of art-recognized techniques for introducing foreignnucleic acid (e.g., DNA) into a host cell, including calcium phosphateor calcium chloride co-precipitation, DEAE-dextran-mediatedtransfection, lipofection, or electroporation. Suitable methods fortransforming or transfecting host cells can be found in Sambrook, et al.(MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring HarborLaboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor,N.Y., 1989), and other laboratory manuals.

[0302] For stable transfection of mammalian cells, it is known that,depending upon the expression vector and transfection technique used,only a small fraction of cells may integrate the foreign DNA into theirgenome. In order to identify and select these integrants, a gene thatencodes a selectable marker (e.g., resistance to antibiotics) isgenerally introduced into the host cells along with the gene ofinterest. Various selectable markers include those that conferresistance to drugs, such as G418, hygromycin and methotrexate. Nucleicacid encoding a selectable marker can be introduced into a host cell onthe same vector as that encoding MOLX or can be introduced on a separatevector. Cells stably transfected with the introduced nucleic acid can beidentified by drug selection (e.g., cells that have incorporated theselectable marker gene will survive, while the other cells die).

[0303] A host cell of the invention, such as a prokaryotic or eukaryotichost cell in culture, can be used to produce (i.e., express) MOLXprotein. Accordingly, the invention further provides methods forproducing MOLX protein using the host cells of the invention. In oneembodiment, the method comprises culturing the host cell of invention(into which a recombinant expression vector encoding MOLX protein hasbeen introduced) in a suitable medium such that MOLX protein isproduced. In another embodiment, the method further comprises isolatingMOLX protein from the medium or the host cell.

[0304] Transgenic MOLX Animals

[0305] The host cells of the invention can also be used to producenon-human transgenic animals. For example, in one embodiment, a hostcell of the invention is a fertilized oocyte or an embryonic stem cellinto which MOLX protein-coding sequences have been introduced. Such hostcells can then be used to create non-human transgenic animals in whichexogenous MOLX sequences have been introduced into their genome orhomologous recombinant animals in which endogenous MOLX sequences havebeen altered. Such animals are useful for studying the function and/oractivity of MOLX protein and for identifying and/or evaluatingmodulators of MOLX protein activity. As used herein, a “transgenicanimal” is a non-human animal, preferably a mammal, more preferably arodent such as a rat or mouse, in which one or more of the cells of theanimal includes a transgene. Other examples of transgenic animalsinclude non-human primates, sheep, dogs, cows, goats, chickens,amphibians, etc. A transgene is exogenous DNA that is integrated intothe genome of a cell from which a transgenic animal develops and thatremains in the genome of the mature animal, thereby directing theexpression of an encoded gene product in one or more cell types ortissues of the transgenic animal. As used herein, a “homologousrecombinant animal” is a non-human animal, preferably a mammal, morepreferably a mouse, in which an endogenous MOLX gene has been altered byhomologous recombination between the endogenous gene and an exogenousDNA molecule introduced into a cell of the animal, e.g., an embryoniccell of the animal, prior to development of the animal.

[0306] A transgenic animal of the invention can be created byintroducing MOLX-encoding nucleic acid into the male pronuclei of afertilized oocyte (e.g., by microinjection, retroviral infection) andallowing the oocyte to develop in a pseudopregnant female foster animal.The human MOLX cDNA sequences of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15,17, 19, 21, and 23 can be introduced as a transgene into the genome of anon-human animal. Alternatively, a non-human homologue of the human MOLXgene, such as a mouse MOLX gene, can be isolated based on hybridizationto the human MOLX cDNA (described further supra) and used as atransgene. Intronic sequences and polyadenylation signals can also beincluded in the transgene to increase the efficiency of expression ofthe transgene. A tissue-specific regulatory sequence(s) can beoperably-linked to the MOLX transgene to direct expression of MOLXprotein to particular cells. Methods for generating transgenic animalsvia embryo manipulation and microinjection, particularly animals such asmice, have become conventional in the art and are described, forexample, in U.S. Pat. Nos. 4,736,866; 4,870,009; and 4,873,191; andHogan, 1986. In: MANIPULATING THE MOUSE EMBRYO, Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y. Similar methods are used forproduction of other transgenic animals. A transgenic founder animal canbe identified based upon the presence of the MOLX transgene in itsgenome and/or expression of MOLX mRNA in tissues or cells of theanimals. A transgenic founder animal can then be used to breedadditional animals carrying the transgene. Moreover, transgenic animalscarrying a transgene-encoding MOLX protein can further be bred to othertransgenic animals carrying other transgenes.

[0307] To create a homologous recombinant animal, a vector is preparedwhich contains at least a portion of an MOLX gene into which a deletion,addition or substitution has been introduced to thereby alter, e.g.,functionally disrupt, the MOLX gene. The MOLX gene can be a human gene(e.g., the cDNA of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and23), but more preferably, is a non-human homologue of a human MOLX gene.For example, a mouse homologue of human MOLX gene of SEQ ID NOS:1, 3, 5,7, 9, 11, 13, 15, 17, 19, 21, and 23 can be used to construct ahomologous recombination vector suitable for altering an endogenous MOLXgene in the mouse genome. In one embodiment, the vector is designed suchthat, upon homologous recombination, the endogenous MOLX gene isfunctionally disrupted (i.e., no longer encodes a functional protein;also referred to as a “knock out” vector).

[0308] Alternatively, the vector can be designed such that, uponhomologous recombination, the endogenous MOLX gene is mutated orotherwise altered but still encodes functional protein (e.g., theupstream regulatory region can be altered to thereby alter theexpression of the endogenous MOLX protein). In the homologousrecombination vector, the altered portion of the MOLX gene is flanked atits 5′- and 3′-termini by additional nucleic acid of the MOLX gene toallow for homologous recombination to occur between the exogenous MOLXgene carried by the vector and an endogenous MOLX gene in an embryonicstem cell. The additional flanking MOLX nucleic acid is of sufficientlength for successful homologous recombination with the endogenous gene.Typically, several kilobases of flanking DNA (both at the 5′- and3′-termini) are included in the vector. See, e.g., Thomas, et al., 1987.Cell 51: 503 for a description of homologous recombination vectors. Thevector is ten introduced into an embryonic stem cell line (e.g., byelectroporation) and cells in which the introduced MOLX gene hashomologously-recombined with the endogenous MOLX gene are selected. See,e.g., Li, et al., 1992. Cell 69: 915.

[0309] The selected cells are then injected into a blastocyst of ananimal (e.g., a mouse) to form aggregation chimeras. See, e.g., Bradley,1987. In: TERATOCARCINOMAS AND EMBRYONIC STEM CELLS: A PRACTICALAPPROACH, Robertson, ed. IRL, Oxford, pp. 113-152. A chimeric embryo canthen be implanted into a suitable pseudopregnant female foster animaland the embryo brought to term. Progeny harboring thehomologously-recombined DNA in their germ cells can be used to breedanimals in which all cells of the animal contain thehomologously-recombined DNA by germline transmission of the transgene.Methods for constructing homologous recombination vectors and homologousrecombinant animals are described further in Bradley, 1991. Curr. Opin.Biotechnol. 2: 823-829; PCT International Publication Nos.: WO 90/11354;WO 91/01140; WO 92/0968; and WO 93/04169.

[0310] In another embodiment, transgenic non-humans animals can beproduced that contain selected systems that allow for regulatedexpression of the transgene. One example of such a system is thecre/loxP recombinase system of bacteriophage P1. For a description ofthe cre/loxP recombinase system, See, e.g., Lakso, et al., 1992. Proc.Natl. Acad. Sci. USA 89: 6232-6236. Another example of a recombinasesystem is the FLP recombinase system of Saccharomyces cerevisiae. See,O'Gorman, et al., 1991. Science 251:1351-1355. If a cre/loxP recombinasesystem is used to regulate expression of the transgene, animalscontaining transgenes encoding both the Cre recombinase and a selectedprotein are required. Such animals can be provided through theconstruction of “double” transgenic animals, e.g., by mating twotransgenic animals, one containing a transgene encoding a selectedprotein and the other containing a transgene encoding a recombinase.

[0311] Clones of the non-human transgenic animals described herein canalso be produced according to the methods described in Wilmut, et al.,1997. Nature 385: 810-813. In brief, a cell (e.g., a somatic cell) fromthe transgenic animal can be isolated and induced to exit the growthcycle and enter Go phase. The quiescent cell can then be fused, e.g.,through the use of electrical pulses, to an enucleated oocyte from ananimal of the same species from which the quiescent cell is isolated.The reconstructed oocyte is then cultured such that it develops tomorula or blastocyte and then transferred to pseudopregnant femalefoster animal. The offspring borne of this female foster animal will bea clone of the animal from which the cell (e.g., the somatic cell) isisolated.

[0312] Pharmaceutical Compositions

[0313] The MOLX nucleic acid molecules, MOLX proteins, and anti-MOLXantibodies (also referred to herein as “active compounds”) of theinvention, and derivatives, fragments, analogs and homologs thereof, canbe incorporated into pharmaceutical compositions suitable foradministration. Such compositions typically comprise the nucleic acidmolecule, protein, or antibody and a pharmaceutically acceptablecarrier. As used herein, “pharmaceutically acceptable carrier” isintended to include any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents, and the like, compatible with pharmaceutical administration.Suitable carriers are described in the most recent edition ofRemington's Pharmaceutical Sciences, a standard reference text in thefield, which is incorporated herein by reference. Preferred examples ofsuch carriers or diluents include, but are not limited to, water,saline, finger's solutions, dextrose solution, and 5% human serumalbumin. Liposomes and non-aqueous vehicles such as fixed oils may alsobe used. The use of such media and agents for pharmaceutically activesubstances is well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the active compound, use thereof inthe compositions is contemplated. Supplementary active compounds canalso be incorporated into the compositions.

[0314] A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical),transmucosal, and rectal administration. Solutions or suspensions usedfor parenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid(EDTA); buffers such as acetates, citrates or phosphates, and agents forthe adjustment of tonicity such as sodium chloride or dextrose. The pHcan be adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

[0315] Pharmaceutical compositions suitable for injectable use includesterile aqueous solutions (where water soluble) or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringeability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as manitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

[0316] Sterile injectable solutions can be prepared by incorporating theactive compound (e.g., an MOLX protein or anti-MOLX antibody) in therequired amount in an appropriate solvent with one or a combination ofingredients enumerated above, as required, followed by filteredsterilization. Generally, dispersions are prepared by incorporating theactive compound into a sterile vehicle that contains a basic dispersionmedium and the required other ingredients from those enumerated above.In the case of sterile powders for the preparation of sterile injectablesolutions, methods of preparation are vacuum drying and freeze-dryingthat yields a powder of the active ingredient plus any additionaldesired ingredient from a previously sterile-filtered solution thereof.

[0317] Oral compositions generally include an inert diluent or an ediblecarrier. They can be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules. Oral compositions can also be preparedusing a fluid carrier for use as a mouthwash, wherein the compound inthe fluid carrier is applied orally and swished and expectorated orswallowed. Pharmaceutically compatible binding agents, and/or adjuvantmaterials can be included as part of the composition. The tablets,pills, capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

[0318] For administration by inhalation, the compounds are delivered inthe form of an aerosol spray from pressured container or dispenser whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

[0319] Systemic administration can also be by transmucosal ortransdermal means. For transmucosal or transdermal administration,penetrants appropriate to the barrier to be permeated are used in theformulation. Such penetrants are generally known in the art, andinclude, for example, for transmucosal administration, detergents, bilesalts, and fusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

[0320] The compounds can also be prepared in the form of suppositories(e.g., with conventional suppository bases such as cocoa butter andother glycerides) or retention enemas for rectal delivery.

[0321] In one embodiment, the active compounds are prepared withcarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

[0322] It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved, and the limitationsinherent in the art of compounding such an active compound for thetreatment of individuals.

[0323] The nucleic acid molecules of the invention can be inserted intovectors and used as gene therapy vectors. Gene therapy vectors can bedelivered to a subject by, for example, intravenous injection, localadministration (see, e.g., U.S. Pat. No. 5,328,470) or by stereotacticinjection (see, e.g., Chen, et al., 1994. Proc. Natl. Acad. Sci. USA 91:3054-3057). The pharmaceutical preparation of the gene therapy vectorcan include the gene therapy vector in an acceptable diluent, or cancomprise a slow release matrix in which the gene delivery vehicle isimbedded. Alternatively, where the complete gene delivery vector can beproduced intact from recombinant cells, e.g., retroviral vectors, thepharmaceutical preparation can include one or more cells that producethe gene delivery system.

[0324] The pharmaceutical compositions can be included in a container,pack, or dispenser together with instructions for administration.

[0325] Screening and Detection Methods

[0326] The isolated nucleic acid molecules of the invention can be usedto express MOLX protein (e.g., via a recombinant expression vector in ahost cell in gene therapy applications), to detect MOLX mRNA (e.g., in abiological sample) or a genetic lesion in an MOLX gene, and to modulateMOLX activity, as described further, below. In addition, the MOLXproteins can be used to screen drugs or compounds that modulate the MOLXprotein activity or expression as well as to treat disorderscharacterized by insufficient or excessive production of MOLX protein orproduction of MOLX protein forms that have decreased or aberrantactivity compared to MOLX wild-type protein (e.g.; diabetes (regulatesinsulin release); obesity (binds and transport lipids); metabolicdisturbances associated with obesity, the metabolic syndrome X as wellas anorexia and wasting disorders associated with chronic diseases andvarious cancers, and infectious disease (possesses anti-microbialactivity) and the various dyslipidemias. In addition, the anti-MOLXantibodies of the invention can be used to detect and isolate MOLXproteins and modulate MOLX activity. In yet a further aspect, theinvention can be used in methods to influence appetite, absorption ofnutrients and the disposition of metabolic substrates in both a positiveand negative fashion.

[0327] The invention further pertains to novel agents identified by thescreening assays described herein and uses thereof for treatments asdescribed, supra.

[0328] Screening Assays

[0329] The invention provides a method (also referred to herein as a“screening assay”) for identifying modulators, i.e., candidate or testcompounds or agents (e.g., peptides, peptidomimetics, small molecules orother drugs) that bind to MOLX proteins or have a stimulatory orinhibitory effect on, e.g., MOLX protein expression or MOLX proteinactivity. The invention also includes compounds identified in thescreening assays described herein.

[0330] In one embodiment, the invention provides assays for screeningcandidate or test compounds which bind to or modulate the activity ofthe membrane-bound form of an MOLX protein or polypeptide orbiologically-active portion thereof. The test compounds of the inventioncan be obtained using any of the numerous approaches in combinatoriallibrary methods known in the art, including: biological libraries;spatially addressable parallel solid phase or solution phase libraries;synthetic library methods requiring deconvolution; the “one-beadone-compound” library method; and synthetic library methods usingaffinity chromatography selection. The biological library approach islimited to peptide libraries, while the other four approaches areapplicable to peptide, non-peptide oligomer or small molecule librariesof compounds. See, e.g., Lam, 1997. Anticancer Drug Design 12: 145.

[0331] A “small molecule” as used herein, is meant to refer to acomposition that has a molecular weight of less than about 5 kD and mostpreferably less than about 4 kD. Small molecules can be, e.g., nucleicacids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids orother organic or inorganic molecules. Libraries of chemical and/orbiological mixtures, such as fungal, bacterial, or algal extracts, areknown in the art and can be screened with any of the assays of theinvention.

[0332] Examples of methods for the synthesis of molecular libraries canbe found in the art, for example in: DeWitt, et al., 1993. Proc. Natl.Acad. Sci. U.S.A. 90: 6909; Erb, et al., 1994. Proc. Natl. Acad. Sci.U.S.A. 91: 11422; Zuckermann, et al., 1994. J. Med. Chem. 37: 2678; Cho,et al., 1993. Science 261: 1303; Carrell, et al., 1994. Angew. Chem.Int. Ed. Engl. 33: 2059; Carell, et al., 1994. Angew. Chem. Int. Ed.Engl. 33: 2061; and Gallop, et al., 1994. J. Med. Chem. 37: 1233.

[0333] Libraries of compounds may be presented in solution (e.g.,Houghten, 1992. Biotechniques 13: 412-421), or on beads (Lam, 1991.Nature 354: 82-84), on chips (Fodor, 1993. Nature 364: 555-556),bacteria (Ladner, U.S. Pat. No. 5,223,409), spores (Ladner, U.S. Pat.No. 5,233,409), plasmids (Cull, et al., 1992. Proc. Natl. Acad. Sci. USA89: 1865-1869) or on phage (Scott and Smith, 1990. Science 249: 386-390;Devlin, 1990. Science 249: 404-406; Cwirla, et al., 1990. Proc. Natl.Acad. Sci. U.S.A. 87: 6378-6382; Felici, 1991. J. Mol. Biol. 222:301-310; Ladner, U.S. Pat. No. 5,233,409.).

[0334] In one embodiment, an assay is a cell-based assay in which a cellwhich expresses a membrane-bound form of MOLX protein, or abiologically-active portion thereof, on the cell surface is contactedwith a test compound and the ability of the test compound to bind to anMOLX protein determined. The cell, for example, can of mammalian originor a yeast cell. Determining the ability of the test compound to bind tothe MOLX protein can be accomplished, for example, by coupling the testcompound with a radioisotope or enzymatic label such that binding of thetest compound to the MOLX protein or biologically-active portion thereofcan be determined by detecting the labeled compound in a complex. Forexample, test compounds can be labeled with ¹²⁵I, ³⁵S, ¹⁴C, or ³H,either directly or indirectly, and the radioisotope detected by directcounting of radioemission or by scintillation counting. Alternatively,test compounds can be enzymatically-labeled with, for example,horseradish peroxidase, alkaline phosphatase, or luciferase, and theenzymatic label detected by determination of conversion of anappropriate substrate to product. In one embodiment, the assay comprisescontacting a cell which expresses a membrane-bound form of MOLX protein,or a biologically-active portion thereof, on the cell surface with aknown compound which binds MOLX to form an assay mixture, contacting theassay mixture with a test compound, and determining the ability of thetest compound to interact with an MOLX protein, wherein determining theability of the test compound to interact with an MOLX protein comprisesdetermining the ability of the test compound to preferentially bind toMOLX protein or a biologically-active portion thereof as compared to theknown compound.

[0335] In another embodiment, an assay is a cell-based assay comprisingcontacting a cell expressing a membrane-bound form of MOLX protein, or abiologically-active portion thereof, on the cell surface with a testcompound and determining the ability of the test compound to modulate(e.g., stimulate or inhibit) the activity of the MOLX protein orbiologically-active portion thereof. Determining the ability of the testcompound to modulate the activity of MOLX or a biologically-activeportion thereof can be accomplished, for example, by determining theability of the MOLX protein to bind to or interact with an MOLX targetmolecule. As used herein, a “target molecule” is a molecule with whichan MOLX protein binds or interacts in nature, for example, a molecule onthe surface of a cell which expresses an MOLX interacting protein, amolecule on the surface of a second cell, a molecule in theextracellular milieu, a molecule associated with the internal surface ofa cell membrane or a cytoplasmic molecule. An MOLX target molecule canbe a non-MOLX molecule or an MOLX protein or polypeptide of theinvention. In one embodiment, an MOLX target molecule is a component ofa signal transduction pathway that facilitates transduction of anextracellular signal (e.g. a signal generated by binding of a compoundto a membrane-bound MOLX molecule) through the cell membrane and intothe cell. The target, for example, can be a second intercellular proteinthat has catalytic activity or a protein that facilitates theassociation of downstream signaling molecules with MOLX.

[0336] Determining the ability of the MOLX protein to bind to orinteract with an MOLX target molecule can be accomplished by one of themethods described above for determining direct binding. In oneembodiment, determining the ability of the MOLX protein to bind to orinteract with an MOLX target molecule can be accomplished by determiningthe activity of the target molecule. For example, the activity of thetarget molecule can be determined by detecting induction of a cellularsecond messenger of the target (i.e. intracellular Ca²⁺, diacylglycerol,IP₃, etc.), detecting catalytic/enzymatic activity of the target anappropriate substrate, detecting the induction of a reporter gene(comprising an MOLX-responsive regulatory element operatively linked toa nucleic acid encoding a detectable marker, e.g., luciferase), ordetecting a cellular response, for example, cell survival, cellulardifferentiation, or cell proliferation.

[0337] In yet another embodiment, an assay of the invention is acell-free assay comprising contacting an MOLX protein orbiologically-active portion thereof with a test compound and determiningthe ability of the test compound to bind to the MOLX protein orbiologically-active portion thereof. Binding of the test compound to theMOLX protein can be determined either directly or indirectly asdescribed above. In one such embodiment, the assay comprises contactingthe MOLX protein or biologically-active portion thereof with a knowncompound which binds MOLX to form an assay mixture, contacting the assaymixture with a test compound, and determining the ability of the testcompound to interact with an MOLX protein, wherein determining theability of the test compound to interact with an MOLX protein comprisesdetermining the ability of the test compound to preferentially bind toMOLX or biologically-active portion thereof as compared to the knowncompound.

[0338] In still another embodiment, an assay is a cell-free assaycomprising contacting MOLX protein or biologically-active portionthereof with a test compound and determining the ability of the testcompound to modulate (e.g. stimulate or inhibit) the activity of theMOLX protein or biologically-active portion thereof. Determining theability of the test compound to modulate the activity of MOLX can beaccomplished, for example, by determining the ability of the MOLXprotein to bind to an MOLX target molecule by one of the methodsdescribed above for determining direct binding. In an alternativeembodiment, determining the ability of the test compound to modulate theactivity of MOLX protein can be accomplished by determining the abilityof the MOLX protein further modulate an MOLX target molecule. Forexample, the catalytic/enzymatic activity of the target molecule on anappropriate substrate can be determined as described, supra.

[0339] In yet another embodiment, the cell-free assay comprisescontacting the MOLX protein or biologically-active portion thereof witha known compound which binds MOLX protein to form an assay mixture,contacting the assay mixture with a test compound, and determining theability of the test compound to interact with an MOLX protein, whereindetermining the ability of the test compound to interact with an MOLXprotein comprises determining the ability of the MOLX protein topreferentially bind to or modulate the activity of an MOLX targetmolecule.

[0340] The cell-free assays of the invention are amenable to use of boththe soluble form or the membrane-bound form of MOLX protein. In the caseof cell-free assays comprising the membrane-bound form of MOLX protein,it may be desirable to utilize a solubilizing agent such that themembrane-bound form of MOLX protein is maintained in solution. Examplesof such solubilizing agents include non-ionic detergents such asn-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside,octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton® X-100,Tritono X-114, Thesit®, Isotridecypoly(ethylene glycol ether),,N-dodecyl—N,N-dimethyl-3-ammonio-1-propane sulfonate,3-(3-cholamidopropyl) dimethylamminiol-1-propane sulfonate (CHAPS), or3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-1-propane sulfonate(CHAPSO).

[0341] In more than one embodiment of the above assay methods of theinvention, it may be desirable to immobilize either MOLX protein or itstarget molecule to facilitate separation of complexed from uncomplexedforms of one or both of the proteins, as well as to accommodateautomation of the assay. Binding of a test compound to MOLX protein, orinteraction of MOLX protein with a target molecule in the presence andabsence of a candidate compound, can be accomplished in any vesselsuitable for containing the reactants. Examples of such vessels includemicrotiter plates, test tubes, and micro-centrifuge tubes. In oneembodiment, a fusion protein can be provided that adds a domain thatallows one or both of the proteins to be bound to a matrix. For example,GST-MOLX fusion proteins or GST-target fusion proteins can be adsorbedonto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) orglutathione derivatized microtiter plates, that are then combined withthe test compound or the test compound and either the non-adsorbedtarget protein or MOLX protein, and the mixture is incubated underconditions conducive to complex formation (e.g., at physiologicalconditions for salt and pH). Following incubation, the beads ormicrotiter plate wells are washed to remove any unbound components, thematrix immobilized in the case of beads, complex determined eitherdirectly or indirectly, for example, as described, supra. Alternatively,the complexes can be dissociated from the matrix, and the level of MOLXprotein binding or activity determined using standard techniques.

[0342] Other techniques for immobilizing proteins on matrices can alsobe used in the screening assays of the invention. For example, eitherthe MOLX protein or its target molecule can be immobilized utilizingconjugation of biotin and streptavidin. Biotinylated MOLX protein ortarget molecules can be prepared from biotin-NHS(N-hydroxy-succinimide)using techniques well-known within the art (e.g., biotinylation kit,Pierce Chemicals, Rockford, Ill.), and immobilized in the wells ofstreptavidin-coated 96 well plates (Pierce Chemical). Alternatively,antibodies reactive with MOLX protein or target molecules, but which donot interfere with binding of the MOLX protein to its target molecule,can be derivatized to the wells of the plate, and unbound target or MOLXprotein trapped in the wells by antibody conjugation. Methods fordetecting such complexes, in addition to those described above for theGST-immobilized complexes, include immunodetection of complexes usingantibodies reactive with the MOLX protein or target molecule, as well asenzyme-linked assays that rely on detecting an enzymatic activityassociated with the MOLX protein or target molecule.

[0343] In another embodiment, modulators of MOLX protein expression areidentified in a method wherein a cell is contacted with a candidatecompound and the expression of MOLX mRNA or protein in the cell isdetermined. The level of expression of MOLX mRNA or protein in thepresence of the candidate compound is compared to the level ofexpression of MOLX mRNA or protein in the absence of the candidatecompound. The candidate compound can then be identified as a modulatorof MOLX mRNA or protein expression based upon this comparison. Forexample, when expression of MOLX mRNA or protein is greater (i.e.,statistically significantly greater) in the presence of the candidatecompound than in its absence, the candidate compound is identified as astimulator of MOLX mRNA or protein expression. Alternatively, whenexpression of MOLX mRNA or protein is less (statistically significantlyless) in the presence of the candidate compound than in its absence, thecandidate compound is identified as an inhibitor of MOLX mRNA or proteinexpression. The level of MOLX mRNA or protein expression in the cellscan be determined by methods described herein for detecting MOLX mRNA orprotein.

[0344] In yet another aspect of the invention, the MOLX proteins can beused as “bait proteins” in a two-hybrid assay or three hybrid assay(see, e.g., U.S. Pat. No. 5,283,317; Zervos, et al., 1993. Cell 72:223-232; Madura, et al., 1993. J. Biol. Chem. 268: 12046-12054; Bartel,et al., 1993. Biotechniques 14: 920-924; Iwabuchi, et al., 1993.Oncogene 8: 1693-1696; and Brent WO 94/10300), to identify otherproteins that bind to or interact with MOLX (“MOLX-binding proteins” or“MOLX-bp”) and modulate MOLX activity. Such MOLX-binding proteins arealso likely to be involved in the propagation of signals by the MOLXproteins as, for example, upstream or downstream elements of the MOLXpathway.

[0345] The two-hybrid system is based on the modular nature of mosttranscription factors, which consist of separable DNA-binding andactivation domains. Briefly, the assay utilizes two different DNAconstructs. In one construct, the gene that codes for MOLX is fused to agene encoding the DNA binding domain of a known transcription factor(e.g., GAL-4). In the other construct, a DNA sequence, from a library ofDNA sequences, that encodes an unidentified protein (“prey” or “sample”)is fused to a gene that codes for the activation domain of the knowntranscription factor. If the “bait” and the “prey” proteins are able tointeract, in vivo, forming an MOLX-dependent complex, the DNA-bindingand activation domains of the transcription factor are brought intoclose proximity. This proximity allows transcription of a reporter gene(e.g., LacZ) that is operably linked to a transcriptional regulatorysite responsive to the transcription factor. Expression of the reportergene can be detected and cell colonies containing the functionaltranscription factor can be isolated and used to obtain the cloned genethat encodes the protein which interacts with MOLX.

[0346] The invention further pertains to novel agents identified by theaforementioned screening assays and uses thereof for treatments asdescribed herein.

[0347] Detection Assays

[0348] Portions or fragments of the cDNA sequences identified herein(and the corresponding complete gene sequences) can be used in numerousways as polynucleotide reagents. By way of example, and not oflimitation, these sequences can be used to: (i) map their respectivegenes on a chromosome; and, thus, locate gene regions associated withgenetic disease; (ii) identify an individual from a minute biologicalsample (tissue typing); and (iii) aid in forensic identification of abiological sample. Some of these applications are described in thesubsections, below.

[0349] Chromosome Mapping

[0350] Once the sequence (or a portion of the sequence) of a gene hasbeen isolated, this sequence can be used to map the location of the geneon a chromosome. This process is called chromosome mapping. Accordingly,portions or fragments of the MOLX sequences, SEQ ID NOS:1, 3, 5, 7, 9,11, 13, 15, 17, 19, 21, and 23, or fragments or derivatives thereof, canbe used to map the location of the MOLX genes, respectively, on achromosome. The mapping of the MOLX sequences to chromosomes is animportant first step in correlating these sequences with genesassociated with disease.

[0351] Briefly, MOLX genes can be mapped to chromosomes by preparing PCRprimers (preferably 15-25 bp in length) from the MOLX sequences.Computer analysis of the MOLX, sequences can be used to rapidly selectprimers that do not span more than one exon in the genomic DNA, thuscomplicating the amplification process. These primers can then be usedfor PCR screening of somatic cell hybrids containing individual humanchromosomes. Only those hybrids containing the human gene correspondingto the MOLX sequences will yield an amplified fragment.

[0352] Somatic cell hybrids are prepared by fusing somatic cells fromdifferent mammals (e.g., human and mouse cells). As hybrids of human andmouse cells grow and divide, they gradually lose human chromosomes inrandom order, but retain the mouse chromosomes. By using media in whichmouse cells cannot grow, because they lack a particular enzyme, but inwhich human cells can, the one human chromosome that contains the geneencoding the needed enzyme will be retained. By using various media,panels of hybrid cell lines can be established. Each cell line in apanel contains either a single human chromosome or a small number ofhuman chromosomes, and a full set of mouse chromosomes, allowing easymapping of individual genes to specific human chromosomes. See, e.g.,D'Eustachio, et al., 1983. Science 220: 919-924. Somatic cell hybridscontaining only fragments of human chromosomes can also be produced byusing human chromosomes with translocations and deletions.

[0353] PCR mapping of somatic cell hybrids is a rapid procedure forassigning a particular sequence to a particular chromosome. Three ormore sequences can be assigned per day using a single thermal cycler.Using the MOLX sequences to design oligonucleotide primers,sub-localization can be achieved with panels of fragments from specificchromosomes.

[0354] Fluorescence in situ hybridization (FISH) of a DNA sequence to ametaphase chromosomal spread can further be used to provide a precisechromosomal location in one step. Chromosome spreads can be made usingcells whose division has been blocked in metaphase by a chemical likecolcemid that disrupts the mitotic spindle. The chromosomes can betreated briefly with trypsin, and then stained with Giemsa. A pattern oflight and dark bands develops on each chromosome, so that thechromosomes can be identified individually. The FISH technique can beused with a DNA sequence as short as 500 or 600 bases. However, cloneslarger than 1,000 bases have a higher likelihood of binding to a uniquechromosomal location with sufficient signal intensity for simpledetection. Preferably 1,000 bases, and more preferably 2,000 bases, willsuffice to get good results at a reasonable amount of time. For a reviewof this technique, see, Verma, et al., HUMAN CHROMOSOMES: A MANUAL OFBASIC TECHNIQUES (Pergamon Press, New York 1988).

[0355] Reagents for chromosome mapping can be used individually to marka single chromosome or a single site on that chromosome, or panels ofreagents can be used for marking multiple sites and/or multiplechromosomes. Reagents corresponding to noncoding regions of the genesactually are preferred for mapping purposes. Coding sequences are morelikely to be conserved within gene families, thus increasing the chanceof cross hybridizations during chromosomal mapping.

[0356] Once a sequence has been mapped to a precise chromosomallocation, the physical position of the sequence on the chromosome can becorrelated with genetic map data. Such data are found, e.g., inMcKusick, MENDELIAN INHERITANCE IN MAN, available on-line through JohnsHopkins University Welch Medical Library). The relationship betweengenes and disease, mapped to the same chromosomal region, can then beidentified through linkage analysis (co-inheritance of physicallyadjacent genes), described in, e.g., Egeland, et al., 1987. Nature, 325:783-787.

[0357] Moreover, differences in the DNA sequences between individualsaffected and unaffected with a disease associated with the MOLX gene,can be determined. If a mutation is observed in some or all of theaffected individuals but not in any unaffected individuals, then themutation is likely to be the causative agent of the particular disease.Comparison of affected and unaffected individuals generally involvesfirst looking for structural alterations in the chromosomes, such asdeletions or translocations that are visible from chromosome spreads ordetectable using PCR based on that DNA sequence. Ultimately, completesequencing of genes from several individuals can be performed to confirmthe presence of a mutation and to distinguish mutations frompolymorphisms.

[0358] Tissue Typing

[0359] The MOLX sequences of the invention can also be used to identifyindividuals from minute biological samples. In this technique, anindividual's genomic DNA is digested with one or more restrictionenzymes, and probed on a Southern blot to yield unique bands foridentification. The sequences of the invention are useful as additionalDNA markers for RFLP (“restriction fragment length polymorphisms,”described in U.S. Pat. No. 5,272,057) Furthermore, the sequences of theinvention can be used to provide an alternative technique thatdetermines the actual base-by-base DNA sequence of selected portions ofan individual's genome. Thus, the MOLX sequences described herein can beused to prepare two PCR primers from the 5′- and 3′-termini of thesequences. These primers can then be used to amplify an individual's DNAand subsequently sequence it.

[0360] Panels of corresponding DNA sequences from individuals, preparedin this manner, can provide unique individual identifications, as eachindividual will have a unique set of such DNA sequences due to allelicdifferences. The sequences of the invention can be used to obtain suchidentification sequences from individuals and from tissue. The MOLXsequences of the invention uniquely represent portions of the humangenome. Allelic variation occurs to some degree in the coding regions ofthese sequences, and to a greater degree in the noncoding regions. It isestimated that allelic variation between individual humans occurs with afrequency of about once per each 500 bases. Much of the allelicvariation is due to single nucleotide polymorphisms (SNPs), whichinclude restriction fragment length polymorphisms (RFLPs).

[0361] Each of the sequences described herein can, to some degree, beused as a standard against which DNA from an individual can be comparedfor identification purposes. Because greater numbers of polymorphismsoccur in the noncoding regions, fewer sequences are necessary todifferentiate individuals. The noncoding sequences can comfortablyprovide positive individual identification with a panel of perhaps 10 to1,000 primers that each yield a noncoding amplified sequence of 1100bases. If predicted coding sequences, such as those in SEQ ID NOS: 1, 3,5, 7, 9, 11, 13, 15, 17, 19, 21, and 23 are used, a more appropriatenumber of primers for positive individual identification would be500-2,000.

[0362] Predictive Medicine

[0363] The invention also pertains to the field of predictive medicinein which diagnostic assays, prognostic assays, pharmacogenomics, andmonitoring clinical trials are used for prognostic (predictive) purposesto thereby treat an individual prophylactically. Accordingly, one aspectof the invention relates to diagnostic assays for determining MOLXprotein and/or nucleic acid expression as well as MOLX activity, in thecontext of a biological sample (e.g., blood, serum, cells, tissue) tothereby determine whether an individual is afflicted with a disease ordisorder, or is at risk of developing a disorder, associated withaberrant MOLX expression or activity. The disorders include metabolicdisorders, diabetes, obesity, infectious disease, anorexia,cancer-associated cachexia, cancer, neurodegenerative disorders,Alzheimer's Disease, Parkinson's Disorder, immune disorders, andhematopoietic disorders, and the various dyslipidemias, metabolicdisturbances associated with obesity, the metabolic syndrome X andwasting disorders associated with chronic diseases and various cancers.The invention also provides for prognostic (or predictive) assays fordetermining whether an individual is at risk of developing a disorderassociated with MOLX protein, nucleic acid expression or activity. Forexample, mutations in an MOLX gene can be assayed in a biologicalsample. Such assays can be used for prognostic or predictive purpose tothereby prophylactically treat an individual prior to the onset of adisorder characterized by or associated with MOLX protein, nucleic acidexpression, or biological activity.

[0364] Another aspect of the invention provides methods for determiningMOLX protein, nucleic acid expression or activity in an individual tothereby select appropriate therapeutic or prophylactic agents for thatindividual (referred to herein as “pharmacogenomics”). Pharmacogenomicsallows for the selection of agents (e.g., drugs) for therapeutic orprophylactic treatment of an individual based on the genotype of theindividual (e.g., the genotype of the individual examined to determinethe ability of the individual to respond to a particular agent.)

[0365] Yet another aspect of the invention pertains to monitoring theinfluence of agents (e.g., drugs, compounds) on the expression oractivity of MOLX in clinical trials.

[0366] These and other agents are described in further detail in thefollowing sections.

[0367] Diagnostic Assays

[0368] An exemplary method for detecting the presence or absence of MOLXin a biological sample involves obtaining a biological sample from atest subject and contacting the biological sample with a compound or anagent capable of detecting MOLX protein or nucleic acid (e.g., mRNA,genomic DNA) that encodes MOLX protein such that the presence of MOLX isdetected in the biological sample. An agent for detecting MOLX mRNA orgenomic DNA is a labeled nucleic acid probe capable of hybridizing toMOLX mRNA or genomic DNA. The nucleic acid probe can be, for example, afull-length MOLX nucleic acid, such as the nucleic acid of SEQ ID NOS:1,3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23, or a portion thereof, suchas an oligonucleotide of at least 15, 30, 50, 100, 250 or 500nucleotides in length and sufficient to specifically hybridize understringent conditions to MOLX mRNA or genomic DNA. Other suitable probesfor use in the diagnostic assays of the invention are described herein.

[0369] An agent for detecting MOLX protein is an antibody capable ofbinding to MOLX protein, preferably an antibody with a detectable label.Antibodies can be polyclonal, or more preferably, monoclonal. An intactantibody, or a fragment thereof (e.g., Fab or F(ab′)₂) can be used. Theterm “labeled”, with regard to the probe or antibody, is intended toencompass direct labeling of the probe or antibody by coupling (i.e.,physically linking) a detectable substance to the probe or antibody, aswell as indirect labeling of the probe or antibody by reactivity withanother reagent that is directly labeled. Examples of indirect labelinginclude detection of a primary antibody using a fluorescently-labeledsecondary antibody and end-labeling of a DNA probe with biotin such thatit can be detected with fluorescently-labeled streptavidin. The term“biological sample” is intended to include tissues, cells and biologicalfluids isolated from a subject, as well as tissues, cells and fluidspresent within a subject. That is, the detection method of the inventioncan be used to detect MOLX mRNA, protein, or genomic DNA in a biologicalsample in vitro as well as in vivo. For example, in vitro techniques fordetection of MOLX mRNA include Northern hybridizations and in situhybridizations. In vitro techniques for detection of MOLX proteininclude enzyme linked immunosorbent assays (ELISAs), Western blots,immunoprecipitations, and immunofluorescence. In vitro techniques fordetection of MOLX genomic DNA include Southern hybridizations.Furthermore, in vivo techniques for detection of MOLX protein includeintroducing into a subject a labeled anti-MOLX antibody. For example,the antibody can be labeled with a radioactive marker whose presence andlocation in a subject can be detected by standard imaging techniques.

[0370] In one embodiment, the biological sample contains proteinmolecules from the test subject. Alternatively, the biological samplecan contain mRNA molecules from the test subject or genomic DNAmolecules from the test subject. A preferred biological sample is aperipheral blood leukocyte sample isolated by conventional means from asubject.

[0371] In another embodiment, the methods further involve obtaining acontrol biological sample from a control subject, contacting the controlsample with a compound or agent capable of detecting MOLX protein, mRNA,or genomic DNA, such that the presence of MOLX protein, mRNA or genomicDNA is detected in the biological sample, and comparing the presence ofMOLX protein, mRNA or genomic DNA in the control sample with thepresence of MOLX protein, mRNA or genomic DNA in the test sample.

[0372] The invention also encompasses kits for detecting the presence ofMOLX in a biological sample. For example, the kit can comprise: alabeled compound or agent capable of detecting MOLX protein or mRNA in abiological sample; means for determining the amount of MOLX in thesample; and means for comparing the amount of MOLX in the sample with astandard. The compound or agent can be packaged in a suitable container.The kit can further comprise instructions for using the kit to detectMOLX protein or nucleic acid.

[0373] Prognostic Assays

[0374] The diagnostic methods described herein can furthermore beutilized to identify subjects having or at risk of developing a diseaseor disorder associated with aberrant MOLX expression or activity. Forexample, the assays described herein, such as the preceding diagnosticassays or the following assays, can be utilized to identify a subjecthaving or at risk of developing a disorder associated with MOLX protein,nucleic acid expression or activity. Alternatively, the prognosticassays can be utilized to identify a subject having or at risk fordeveloping a disease or disorder. Thus, the invention provides a methodfor identifying a disease or disorder associated with aberrant MOLXexpression or activity in which a test sample is obtained from a subjectand MOLX protein or nucleic acid (e.g., mRNA, genomic DNA) is detected,wherein the presence of MOLX protein or nucleic acid is diagnostic for asubject having or at risk of developing a disease or disorder associatedwith aberrant MOLX expression or activity. As used herein, a “testsample” refers to a biological sample obtained from a subject ofinterest. For example, a test sample can be a biological fluid (e.g.,serum), cell sample, or tissue.

[0375] Furthermore, the prognostic assays described herein can be usedto determine whether a subject can be administered an agent (e.g., anagonist, antagonist, peptidomimetic, protein, peptide, nucleic acid,small molecule, or other drug candidate) to treat a disease or disorderassociated with aberrant MOLX expression or activity. For example, suchmethods can be used to determine whether a subject can be effectivelytreated with an agent for a disorder. Thus, the invention providesmethods for determining whether a subject can be effectively treatedwith an agent for a disorder associated with aberrant MOLX expression oractivity in which a test sample is obtained and MOLX protein or nucleicacid is detected (e.g., wherein the presence of MOLX protein or nucleicacid is diagnostic for a subject that can be administered the agent totreat a disorder associated with aberrant MOLX expression or activity).

[0376] The methods of the invention can also be used to detect geneticlesions in an MOLX gene, thereby determining if a subject with thelesioned gene is at risk for a disorder characterized by aberrant cellproliferation and/or differentiation. In various embodiments, themethods include detecting, in a sample of cells from the subject, thepresence or absence of a genetic lesion characterized by at least one ofan alteration affecting the integrity of a gene encoding anMOLX-protein, or the misexpression of the MOLX gene. For example, suchgenetic lesions can be detected by ascertaining the existence of atleast one of: (i) a deletion of one or more nucleotides from an MOLXgene; (ii) an addition of one or more nucleotides to an MOLX gene; (iii)a substitution of one or more nucleotides of an MOLX gene, (iv) achromosomal rearrangement of an MOLX gene; (v) an alteration in thelevel of a messenger RNA transcript of an MOLX gene, (vi) aberrantmodification of an MOLX gene, such as of the methylation pattern of thegenomic DNA, (vii) the presence of a non-wild-type splicing pattern of amessenger RNA transcript of an MOLX gene, (viii) a non-wild-type levelof an MOLX protein, (ix) allelic loss of an MOLX gene, and (x)inappropriate post-translational modification of an MOLX protein. Asdescribed herein, there are a large number of assay techniques known inthe art which can be used for detecting lesions in an MOLX gene. Apreferred biological sample is a peripheral blood leukocyte sampleisolated by conventional means from a subject. However, any biologicalsample containing nucleated cells may be used, including, for example,buccal mucosal cells.

[0377] In certain embodiments, detection of the lesion involves the useof a probe/primer in a polymerase chain reaction (PCR) (see, e.g., U.S.Pat. Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or,alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran,et al., 1988. Science 241: 1077-1080; and Nakazawa, et al., 1994. Proc.Natl. Acad. Sci. USA 91: 360-364), the latter of which can beparticularly useful for detecting point mutations in the MOLX-gene (see,Abravaya, et al., 1995. Nucl. Acids Res. 23: 675-682). This method caninclude the steps of collecting a sample of cells from a patient,isolating nucleic acid (e.g., genomic, mRNA or both) from the cells ofthe sample, contacting the nucleic acid sample with one or more primersthat specifically hybridize to an MOLX gene under conditions such thathybridization and amplification of the MOLX gene (if present) occurs,and detecting the presence or absence of an amplification product, ordetecting the size of the amplification product and comparing the lengthto a control sample. It is anticipated that PCR and/or LCR may bedesirable to use as a preliminary amplification step in conjunction withany of the techniques used for detecting mutations described herein.

[0378] Alternative amplification methods include: self sustainedsequence replication (see, Guatelli, et al., 1990. Proc. Natl. Acad.Sci. USA 87: 1874-1878), transcriptional amplification system (see,Kwoh, et al., 1989. Proc. Natl. Acad. Sci. USA 86: 1173-1177); QβReplicase (see, Lizardi, et al, 1988. BioTechnology 6: 1197), or anyother nucleic acid amplification method, followed by the detection ofthe amplified molecules using techniques well known to those of skill inthe art. These detection schemes are especially useful for the detectionof nucleic acid molecules if such molecules are present in very lownumbers.

[0379] In an alternative embodiment, mutations in an MOLX gene from asample cell can be identified by alterations in restriction enzymecleavage patterns. For example, sample and control DNA is isolated,amplified (optionally), digested with one or more restrictionendonucleases, and fragment length sizes are determined by gelelectrophoresis and compared. Differences in fragment length sizesbetween sample and control DNA indicates mutations in the sample DNA.Moreover, the use of sequence specific ribozymes (see, e.g., U.S. Pat.No. 5,493,531) can be used to score for the presence of specificmutations by development or loss of a ribozyme cleavage site.

[0380] In other embodiments, genetic mutations in MOLX can be identifiedby hybridizing a sample and control nucleic acids, e.g., DNA or RNA, tohigh-density arrays containing hundreds or thousands of oligonucleotidesprobes. See, e.g., Cronin, et al., 1996. Human Mutation 7: 244-255;Kozal, et al., 1996. Nat. Med. 2: 753-759. For example, geneticmutations in MOLX can be identified in two dimensional arrays containinglight-generated DNA probes as described in Cronin, et al., supra.Briefly, a first hybridization array of probes can be used to scanthrough long stretches of DNA in a sample and control to identify basechanges between the sequences by making linear arrays of sequentialoverlapping probes. This step allows the identification of pointmutations. This is followed by a second hybridization array that allowsthe characterization of specific mutations by using smaller, specializedprobe arrays complementary to all variants or mutations detected. Eachmutation array is composed of parallel probe sets, one complementary tothe wild-type gene and the other complementary to the mutant gene.

[0381] In yet another embodiment, any of a variety of sequencingreactions known in the art can be used to directly sequence the MOLXgene and detect mutations by comparing the sequence of the sample MOLXwith the corresponding wild-type (control) sequence. Examples ofsequencing reactions include those based on techniques developed byMaxim and Gilbert, 1977. Proc. Natl. Acad. Sci. USA 74: 560 or Sanger,1977. Proc. Natl. Acad. Sci. USA 74: 5463. It is also contemplated thatany of a variety of automated sequencing procedures can be utilized whenperforming the diagnostic assays (see, e.g., Naeve, et al., 1995.Biotechniques 19: 448), including sequencing by mass spectrometry (see,e.g., PCT International Publication No. WO 94/16101; Cohen, et al.,1996. Adv. Chromatography 36: 127-162; and Griffin, et al., 1993. Appl.Biochem. Biotechnol. 38: 147-159).

[0382] Other methods for detecting mutations in the MOLX gene includemethods in which protection from cleavage agents is used to detectmismatched bases in RNA/RNA or RNA/DNA heteroduplexes. See, e.g., Myers,et al., 1985. Science 230: 1242. In general, the art technique of“mismatch cleavage” starts by providing heteroduplexes of formed byhybridizing (labeled) RNA or DNA containing the wild-type MOLX sequencewith potentially mutant RNA or DNA obtained from a tissue sample. Thedouble-stranded duplexes are treated with an agent that cleavessingle-stranded regions of the duplex such as which will exist due tobasepair mismatches between the control and sample strands. Forinstance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybridstreated with S1 nuclease to enzymatically digesting the mismatchedregions. In other embodiments, either DNA/DNA or RNA/DNA duplexes can betreated with hydroxylamine or osmium tetroxide and with piperidine inorder to digest mismatched regions. After digestion of the mismatchedregions, the resulting material is then separated by size on denaturingpolyacrylamide gels to determine the site of mutation. See, e.g.,Cotton, et al., 1988. Proc. Natl. Acad. Sci. USA 85: 4397; Saleeba, etal., 1992. Methods Enzymol. 217: 286-295. In an embodiment, the controlDNA or RNA can be labeled for detection.

[0383] In still another embodiment, the mismatch cleavage reactionemploys one or more proteins that recognize mismatched base pairs indouble-stranded DNA (so called “DNA mismatch repair” enzymes) in definedsystems for detecting and mapping point mutations in MOLX cDNAs obtainedfrom samples of cells. For example, the mutY enzyme of E. coli cleaves Aat G/A mismatches and the thymidine DNA glycosylase from HeLa cellscleaves T at G/T mismatches. See, e.g., Hsu, et al., 1994.Carcinogenesis 15: 1657-1662. According to an exemplary embodiment, aprobe based on an MOLX sequence, e.g., a wild-type MOLX sequence, ishybridized to a cDNA or other DNA product from a test cell(s). Theduplex is treated with a DNA mismatch repair enzyme, and the cleavageproducts, if any, can be detected from electrophoresis protocols or thelike. See, e.g., U.S. Pat. No. 5,459,039.

[0384] In other embodiments, alterations in electrophoretic mobilitywill be used to identify mutations in MOLX genes. For example, singlestrand conformation polymorphism (SSCP) may be used to detectdifferences in electrophoretic mobility between mutant and wild typenucleic acids. See, e.g., Orita, et al., 1989. Proc. Natl. Acad. Sci.USA: 86: 2766; Cotton, 1993. Mutat. Res. 285: 125-144; Hayashi, 1992.Genet. Anal. Tech. Appl. 9: 73-79. Single-stranded DNA fragments ofsample and control MOLX nucleic acids will be denatured and allowed torenature. The secondary structure of single-stranded nucleic acidsvaries according to sequence, the resulting alteration inelectrophoretic mobility enables the detection of even a single basechange. The DNA fragments may be labeled or detected with labeledprobes. The sensitivity of the assay may be enhanced by using RNA(rather than DNA), in which the secondary structure is more sensitive toa change in sequence. In one embodiment, the subject method utilizesheteroduplex analysis to separate double stranded heteroduplex moleculeson the basis of changes in electrophoretic mobility. See, e.g., Keen, etal., 1991. Trends Genet. 7: 5.

[0385] In yet another embodiment, the movement of mutant or wild-typefragments in polyacrylamide gels containing a gradient of denaturant isassayed using denaturing gradient gel electrophoresis (DGGE). See, e.g.,Myers, et al., 1985. Nature 313: 495. When DGGE is used as the method ofanalysis, DNA will be modified to insure that it does not completelydenature, for example by adding a GC clamp of approximately 40 bp ofhigh-melting GC-rich DNA by PCR. In a further embodiment, a temperaturegradient is used in place of a denaturing gradient to identifydifferences in the mobility of control and sample DNA. See, e.g.,Rosenbaum and Reissner, 1987. Biophys. Chems. 265: 12753.

[0386] Examples of other techniques for detecting point mutationsinclude, but are not limited to, selective oligonucleotidehybridization, selective amplification, or selective primer extension.For example, oligonucleotide primers may be prepared in which the knownmutation is placed centrally and then hybridized to target DNA underconditions that permit hybridization only if a perfect match is found.See, e.g., Saiki, et al., 1986. Nature 324: 163; Saiki, et al., 1989.Proc. Natl. Acad. Sci. USA 86: 6230. Such allele specificoligonucleotides are hybridized to PCR amplified target DNA or a numberof different mutations when the oligonucleotides are attached to thehybridizing membrane and hybridized with labeled target DNA.

[0387] Alternatively, allele specific amplification technology thatdepends on selective PCR amplification may be used in conjunction withthe instant invention. Oligonucleotides used as primers for specificamplification may carry the mutation of interest in the center of themolecule (so that amplification depends on differential hybridization;see, e.g., Gibbs, et al., 1989. Nucl. Acids Res. 17: 2437-2448) or atthe extreme 3′-terminus of one primer where, under appropriateconditions, mismatch can prevent, or reduce polymerase extension (see,e.g., Prossner, 1993. Tibtech. 11: 238). In addition it may be desirableto introduce a novel restriction site in the region of the mutation tocreate cleavage-based detection. See, e.g., Gasparini, et al., 1992.Mol. Cell Probes 6: 1. It is anticipated that in certain embodimentsamplification may also be performed using Taq ligase for amplification.See, e.g., Barany, 1991. Proc. Natl. Acad. Sci. USA 88: 189. In suchcases, ligation will occur only if there is a perfect match at the3′-terminus of the 5′ sequence, making it possible to detect thepresence of a known mutation at a specific site by looking for thepresence or absence of amplification.

[0388] The methods described herein may be performed, for example, byutilizing pre-packaged diagnostic kits comprising at least one probenucleic acid or antibody reagent described herein, which may beconveniently used, e.g., in clinical settings to diagnose patientsexhibiting symptoms or family history of a disease or illness involvingan MOLX gene.

[0389] Furthermore, any cell type or tissue, preferably peripheral bloodleukocytes, in which MOLX is expressed may be utilized in the prognosticassays described herein. However, any biological sample containingnucleated cells may be used, including, for example, buccal mucosalcells.

[0390] Pharmacogenomics

[0391] Agents, or modulators that have a stimulatory or inhibitoryeffect on MOLX activity (e.g., MOLX gene expression), as identified by ascreening assay described herein can be administered to individuals totreat (prophylactically or therapeutically) disorders (The disordersinclude metabolic disorders, diabetes, obesity, infectious disease,anorexia, cancer-associated cachexia, cancer, neurodegenerativedisorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders,and hematopoietic disorders, and the various dyslipidemias, metabolicdisturbances associated with obesity, the metabolic syndrome X andwasting disorders associated with chronic diseases and various cancers.)In conjunction with such treatment, the pharmacogenomics (i.e., thestudy of the relationship between an individual's genotype and thatindividual's response to a foreign compound or drug) of the individualmay be considered. Differences in metabolism of therapeutics can lead tosevere toxicity or therapeutic failure by altering the relation betweendose and blood concentration of the pharmacologically active drug. Thus,the pharmacogenomics of the individual permits the selection ofeffective agents (e.g., drugs) for prophylactic or therapeutictreatments based on a consideration of the individual's genotype. Suchpharmacogenomics can further be used to determine appropriate dosagesand therapeutic regimens. Accordingly, the activity of MOLX protein,expression of MOLX nucleic acid, or mutation content of MOLX genes in anindividual can be determined to thereby select appropriate agent(s) fortherapeutic or prophylactic treatment of the individual.

[0392] Pharmacogenomics deals with clinically significant hereditaryvariations in the response to drugs due to altered drug disposition andabnormal action in affected persons. See e.g., Eichelbaum, 1996. Clin.Exp. Pharmacol. Physiol., 23: 983-985; Linder, 1997. Clin. Chem., 43:254-266. In general, two types of pharmacogenetic conditions can bedifferentiated. Genetic conditions transmitted as a single factoraltering the way drugs act on the body (altered drug action) or geneticconditions transmitted as single factors altering the way the body actson drugs (altered drug metabolism). These pharmacogenetic conditions canoccur either as rare defects or as polymorphisms. For example,glucose-6-phosphate dehydrogenase (G6PD) deficiency is a commoninherited enzymopathy in which the main clinical complication ishemolysis after ingestion of oxidant drugs (anti-malarials,sulfonamides, analgesics, nitrofurans) and consumption of fava beans.

[0393] As an illustrative embodiment, the activity of drug metabolizingenzymes is a major determinant of both the intensity and duration ofdrug action. The discovery of genetic polymorphisms of drug metabolizingenzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochrome P450 enzymesCYP2D6 and CYP2C19) has provided an explanation as to why some patientsdo not obtain the expected drug effects or show exaggerated drugresponse and serious toxicity after taking the standard and safe dose ofa drug. These polymorphisms are expressed in two phenotypes in thepopulation, the extensive metabolizer (EM) and poor metabolizer (PM).The prevalence of PM is different among different populations. Forexample, the gene coding for CYP2D6 is highly polymorphic and severalmutations have been identified in PM, which all lead to the absence offunctional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quitefrequently experience exaggerated drug response and side effects whenthey receive standard doses. If a metabolite is the active therapeuticmoiety, PM show no therapeutic response, as demonstrated for theanalgesic effect of codeine mediated by its CYP2D6-formed metabolitemorphine. At the other extreme are the so called ultra-rapidmetabolizers who do not respond to standard doses. Recently, themolecular basis of ultra-rapid metabolism has been identified to be dueto CYP2D6 gene amplification.

[0394] Thus, the activity of MOLX protein, expression of MOLX nucleicacid, or mutation content of MOLX genes in an individual can bedetermined to thereby select appropriate agent(s) for therapeutic orprophylactic treatment of the individual. In addition, pharmacogeneticstudies can be used to apply genotyping of polymorphic alleles encodingdrug-metabolizing enzymes to the identification of an individual's drugresponsiveness phenotype. This knowledge, when applied to dosing or drugselection, can avoid adverse reactions or therapeutic failure and thusenhance therapeutic or prophylactic efficiency when treating a subjectwith an MOLX modulator, such as a modulator identified by one of theexemplary screening assays described herein.

[0395] Monitoring of Effects During Clinical Trials

[0396] Monitoring the influence of agents (e.g., drugs, compounds) onthe expression or activity of MOLX (e.g., the ability to modulateaberrant cell proliferation and/or differentiation) can be applied notonly in basic drug screening, but also in clinical trials. For example,the effectiveness of an agent determined by a screening assay asdescribed herein to increase MOLX gene expression, protein levels, orupregulate MOLX activity, can be monitored in clinical trails ofsubjects exhibiting decreased MOLX gene expression, protein levels, ordownregulated MOLX activity. Alternatively, the effectiveness of anagent determined by a screening assay to decrease MOLX gene expression,protein levels, or downregulate MOLX activity, can be monitored inclinical trails of subjects exhibiting increased MOLX gene expression,protein levels, or upregulated MOLX activity. In such clinical trials,the expression or activity of MOLX and, preferably, other genes thathave been implicated in, for example, a cellular proliferation or immunedisorder can be used as a “read out” or markers of the immuneresponsiveness of a particular cell.

[0397] By way of example, and not of limitation, genes, including MOLX,that are modulated in cells by treatment with an agent (e.g., compound,drug or small molecule) that modulates MOLX activity (e.g., identifiedin a screening assay as described herein) can be identified. Thus, tostudy the effect of agents on cellular proliferation disorders, forexample, in a clinical trial, cells can be isolated and RNA prepared andanalyzed for the levels of expression of MOLX and other genes implicatedin the disorder. The levels of gene expression (i.e., a gene expressionpattern) can be quantified by Northern blot analysis or RT-PCR, asdescribed herein, or alternatively by measuring the amount of proteinproduced, by one of the methods as described herein, or by measuring thelevels of activity of MOLX or other genes. In this manner, the geneexpression pattern can serve as a marker, indicative of thephysiological response of the cells to the agent. Accordingly, thisresponse state may be determined before, and at various points during,treatment of the individual with the agent.

[0398] In one embodiment, the invention provides a method for monitoringthe effectiveness of treatment of a subject with an agent (e.g., anagonist, antagonist, protein, peptide, peptidomimetic, nucleic acid,small molecule, or other drug candidate identified by the screeningassays described herein) comprising the steps of (i) obtaining apre-administration sample from a subject prior to administration of theagent; (ii) detecting the level of expression of an MOLX protein, mRNA,or genomic DNA in the preadministration sample; (iii) obtaining one ormore post-administration samples from the subject; (iv) detecting thelevel of expression or activity of the MOLX protein, mRNA, or genomicDNA in the post-administration samples; (v) comparing the level ofexpression or activity of the MOLX protein, mRNA, or genomic DNA in thepre-administration sample with the MOLX protein, mRNA, or genomic DNA inthe post administration sample or samples; and (vi) altering theadministration of the agent to the subject accordingly. For example,increased administration of the agent may be desirable to increase theexpression or activity of MOLX to higher levels than detected, i.e., toincrease the effectiveness of the agent. Alternatively, decreasedadministration of the agent may be desirable to decrease expression oractivity of MOLX to lower levels than detected, i.e., to decrease theeffectiveness of the agent.

[0399] Methods of Treatment

[0400] The invention provides for both prophylactic and therapeuticmethods of treating a subject at risk of (or susceptible to) a disorderor having a disorder associated with aberrant MOLX expression oractivity. The disorders include cardiomyopathy, atherosclerosis,hypertension, congenital heart defects, aortic stenosis, atrial septaldefect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus,pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD),valve diseases, tuberous sclerosis, scleroderma, obesity,transplantation, adrenoleukodystrophy, congenital adrenal hyperplasia,prostate cancer, neoplasm; adenocarcinoma, lymphoma, uterus cancer,fertility, hemophilia, hypercoagulation, idiopathic thrombocytopenicpurpura, immunodeficiencies, graft versus host disease, AIDS, bronchialasthma, Crohn's disease; multiple sclerosis, treatment of AlbrightHereditary Ostoeodystrophy, and other diseases, disorders and conditionsof the like.

[0401] These methods of treatment will be discussed more fully, below.

[0402] Disease and Disorders

[0403] Diseases and disorders that are characterized by increased(relative to a subject not suffering from the disease or disorder)levels or biological activity may be treated with Therapeutics thatantagonize (i.e., reduce or inhibit) activity. Therapeutics thatantagonize activity may be administered in a therapeutic or prophylacticmanner. Therapeutics that may be utilized include, but are not limitedto: (i) an aforementioned peptide, or analogs, derivatives, fragments orhomologs thereof; (ii) antibodies to an aforementioned peptide; (iii)nucleic acids encoding an aforementioned peptide; (iv) administration ofantisense nucleic acid and nucleic acids that are “dysfunctional” (i.e.,due to a heterologous insertion within the coding sequences of codingsequences to an aforementioned peptide) that are utilized to “knockout”endoggenous function of an aforementioned peptide by homologousrecombination (see, e.g., Capecchi, 1989. Science 244: 1288-1292); or(v) modulators (i.e., inhibitors, agonists and antagonists, includingadditional peptide mimetic of the invention or antibodies specific to apeptide of the invention) that alter the interaction between anaforementioned peptide and its binding partner.

[0404] Diseases and disorders that are characterized by decreased(relative to a subject not suffering from the disease or disorder)levels or biological activity may be treated with Therapeutics thatincrease (i.e., are agonists to) activity. Therapeutics that upregulateactivity may be administered in a therapeutic or prophylactic manner.Therapeutics that may be utilized include, but are not limited to, anaforementioned peptide, or analogs, derivatives, fragments or homologsthereof; or an agonist that increases bioavailability.

[0405] Increased or decreased levels can be readily detected byquantifying peptide and/or RNA, by obtaining a patient tissue sample(e.g., from biopsy tissue) and assaying it in vitro for RNA or peptidelevels, structure and/or activity of the expressed peptides (or mRNAs ofan aforementioned peptide). Methods that are well-known within the artinclude, but are not limited to, immunoassays (e.g., by Western blotanalysis, immunoprecipitation followed by sodium dodecyl sulfate (SDS)polyacrylamide gel electrophoresis, immunocytochemistry, etc.) and/orhybridization assays to detect expression of mRNAs (e.g., Northernassays, dot blots, in situ hybridization, and the like).

[0406] Prophylactic Methods

[0407] In one aspect, the invention provides a method for preventing, ina subject, a disease or condition associated with an aberrant MOLXexpression or activity, by administering to the subject an agent thatmodulates MOLX expression or at least one MOLX activity. Subjects atrisk for a disease that is caused or contributed to by aberrant MOLXexpression or activity can be identified by, for example, any or acombination of diagnostic or prognostic assays as described herein.Administration of a prophylactic agent can occur prior to themanifestation of symptoms characteristic of the MOLX aberrancy, suchthat a disease or disorder is prevented or, alternatively, delayed inits progression. Depending upon the type of MOLX aberrancy, for example,an MOLX agonist or MOLX antagonist agent can be used for treating thesubject. The appropriate agent can be determined based on screeningassays described herein. The prophylactic methods of the invention arefurther discussed in the following subsections.

[0408] Therapeutic Methods

[0409] Another aspect of the invention pertains to methods of modulatingMOLX expression or activity for therapeutic purposes. The modulatorymethod of the invention involves contacting a cell with an agent thatmodulates one or more of the activities of MOLX protein activityassociated with the cell. An agent that modulates MOLX protein activitycan be an agent as described herein, such as a nucleic acid or aprotein, a naturally-occurring cognate ligand of an MOLX protein, apeptide, an MOLX peptidomimetic, or other small molecule. In oneembodiment, the agent stimulates one or more MOLX protein activity.Examples of such stimulatory agents include active MOLX protein and anucleic acid molecule encoding MOLX that has been introduced into thecell. In another embodiment, the agent inhibits one or more MOLX proteinactivity. Examples of such inhibitory agents include antisense MOLXnucleic acid molecules and anti-MOLX antibodies. These modulatorymethods can be performed in vitro (e.g., by culturing the cell with theagent) or, alternatively, in vivo (e.g., by administering the agent to asubject). As such, the invention provides methods of treating anindividual afflicted with a disease or disorder characterized byaberrant expression or activity of an MOLX protein or nucleic acidmolecule. In one embodiment, the method involves administering an agent(e.g., an agent identified by a screening assay described herein), orcombination of agents that modulates (e.g., up-regulates ordown-regulates) MOLX expression or activity. In another embodiment, themethod involves administering an MOLX protein or nucleic acid moleculeas therapy to compensate for reduced or aberrant MOLX expression oractivity.

[0410] Stimulation of MOLX activity is desirable in situations in whichMOLX is abnormally downregulated and/or in which increased MOLX activityis likely to have a beneficial effect. One example of such a situationis where a subject has a disorder characterized by aberrant cellproliferation and/or differentiation (e.g., cancer or immune associateddisorders). Another example of such a situation is where the subject hasa gestational disease (e.g., preclampsia).

[0411] Determination of the Biological Effect of the Therapeutic

[0412] In various embodiments of the invention, suitable in vitro or invivo assays are performed to determine the effect of a specificTherapeutic and whether its administration is indicated for treatment ofthe affected tissue.

[0413] In various specific embodiments, in vitro assays may be performedwith representative cells of the type(s) involved in the patient'sdisorder, to determine if a given Therapeutic exerts the desired effectupon the cell type(s). Compounds for use in therapy may be tested insuitable animal model systems including, but not limited to rats, mice,chicken, cows, monkeys, rabbits, and the like, prior to testing in humansubjects. Similarly, for in vivo testing, any of the animal model systemknown in the art may be used prior to administration to human subjects.

[0414] Prophylactic and Therapeutic Uses of the Compositions of theInvention

[0415] The MOLX nucleic acids and proteins of the invention are usefulin potential prophylactic and therapeutic applications implicated in avariety of disorders including, but not limited to: metabolic disorders,diabetes, obesity, infectious disease, anorexia, cancer-associatedcancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson'sDisorder, immune disorders, hematopoietic disorders, and the variousdyslipidemias, metabolic disturbances associated with obesity, themetabolic syndrome X and wasting disorders associated with chronicdiseases and various cancers.

[0416] As an example, a cDNA encoding the MOLX protein of the inventionmay be useful in gene therapy, and the protein may be useful whenadministered to a subject in need thereof. By way of non-limitingexample, the compositions of the invention will have efficacy fortreatment of patients suffering from: metabolic disorders, diabetes,obesity, infectious disease, anorexia, cancer-associated cachexia,cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson'sDisorder, immune disorders, hematopoietic disorders, and the variousdyslipidemias.

[0417] Both the novel nucleic acid encoding the MOLX protein, and theMOLX protein of the invention, or fragments thereof, may also be usefulin diagnostic applications, wherein the presence or amount of thenucleic acid or the protein are to be assessed. A further use could beas an anti-bacterial molecule (i.e., some peptides have been found topossess anti-bacterial properties). These materials are further usefulin the generation of antibodies which immunospecifically-bind to thenovel substances of the invention for use in therapeutic or diagnosticmethods.

EXAMPLES Example 1 Quantitative Expression Analysis of Clones in VariousCells and Tissues

[0418] The quantitative expression of various clones was assessed usingmicrotiter plates containing RNA samples from a variety of normal andpathology-derived cells, cell lines and tissues using real timequantitative PCR (RTQ PCR; TAQMAN®). RTQ PCR was performed on aPerkin-Elmer Biosystems ABI PRISM® 7700 Sequence Detection System.Various collections of samples are assembled on the plates, and referredto as Panel 1 (containing cells and cell lines from normal and cancersources), Panel 2 (containing samples derived from tissues, inparticular from surgical samples, from normal and cancer sources), Panel3 (containing samples derived from a wide variety of cancer sources),Panel 4 (containing cells and cell lines from normal cells and cellsrelated to inflammatory conditions) and Panel CNSD.01 (containingsamples from normal and diseased brains).

[0419] First, the RNA samples were normalized to constitutivelyexpressed genes such as β-actin and GAPDH. RNA (˜50 ng total or ˜1 ngpolyA+) was converted to cDNA using the TAQMAN® Reverse TranscriptionReagents Kit (PE Biosystems, Foster City, Calif.; Catalog No. N808-0234)and random hexamers according to the manufacturer's protocol. Reactionswere performed in 20 ul and incubated for 30 min. at 48° C. cDNA (5 ul)was then transferred to a separate plate for the TAQMAN® reaction usingβ-actin and GAPDH TAQMAN® Assay Reagents (PE Biosystems; Catalog Nos.4310881E and 4310884E, respectively) and TAQMAN® universal PCR MasterMix (PE Biosystems; Catalog No. 4304447) according to the manufacturer'sprotocol. Reactions were performed in 25 ul using the followingparameters: 2 min. at 50° C.; 10 min. at 95° C.; 15 sec. at 95° C./1min. at 60° C. (40 cycles). Results were recorded as CT values (cycle atwhich a given sample crosses a threshold level of fluorescence) using alog scale, with the difference in RNA concentration between a givensample and the sample with the lowest CT value being represented as 2 tothe power of delta CT. The percent relative expression is then obtainedby taking the reciprocal of this RNA difference and multiplying by 100.The average CT values obtained for 6-actin and GAPDH were used tonormalize RNA samples. The RNA sample generating the highest CT valuerequired no further diluting, while all other samples were dilutedrelative to this sample according to their, β-actin/GAPDH average CTvalues.

[0420] Normalized RNA (5 ul) was converted to cDNA and analyzed viaTAQMAN® using One Step RT-PCR Master Mix Reagents (PE Biosystems;Catalog No. 4309169) and gene-specific primers according to themanufacturer's instructions. Probes and primers were designed for eachassay according to Perkin Elmer Biosystem's Primer Express Softwarepackage (version I for Apple Computer's Macintosh Power PC) or a similaralgorithm using the target sequence as input. Default settings were usedfor reaction conditions and the following parameters were set beforeselecting primers: primer concentration=250 nM, primer meltingtemperature (T_(m)) range=58°-60° C., primer optimal T_(m)=59° C.,maximum primer difference=2° C., probe does not have 5′ G, probe T_(m)must be 10° C. greater than primer T_(m), amplicon size 75 bp to 100 bp.The probes and primers selected (see below) were synthesized bySynthegen (Houston, Tex., USA). Probes were double purified by HPLC toremove uncoupled dye and evaluated by mass spectroscopy to verifycoupling of reporter and quencher dyes to the 5′ and 3′ ends of theprobe, respectively. Their final concentrations were: forward andreverse primers, 900 nM each, and probe, 200 nM.

[0421] PCR conditions:

[0422] Normalized RNA from each tissue and each cell line was spotted ineach well of a 96 well PCR plate (Perkin Elmer Biosystems). PCRcocktails including two probes (a probe specific for the target cloneand another gene-specific probe multiplexed with the target probe) wereset up using 1×TaqManT PCR Master Mix for the PE Biosystems 7700, with 5mM MgCl2, dNTPs (dA, G, C, U at 1:1:1:2 ratios), 0.25 U/ml AmpliTaqGold™ (PE Biosystems), and 0.4 U/□l RNase inhibitor, and 0.25 U/μlreverse transcriptase. Reverse transcription was performed at 48° C. for30 minutes followed by amplification/PCR cycles as follows: 95° C. 10min, then 40 cycles of 95° C. for 15 seconds, 60° C. for 1 minute.

[0423] In the results for Panel 1, the following abbreviations are used:

[0424] ca.=carcinoma,

[0425] *=established from metastasis,

[0426] met=metastasis,

[0427] s cell var=small cell variant,

[0428] non-s=non-sm=non-small,

[0429] squam=squamous,

[0430] pl. eff=pl effusion=pleural effusion,

[0431] glio=glioma,

[0432] astro=astrocytoma, and

[0433] neuro=neuroblastoma.

[0434] Panel 2

[0435] The plates for Panel 2 generally include 2 control wells and 94test samples composed of RNA or cDNA isolated from human tissue procuredby surgeons working in close cooperation with the National CancerInstitute's Cooperative Human Tissue Network (CHTN) or the NationalDisease Research Initiative (NDR1). The tissues are derived from humanmalignancies and in cases where indicated many malignant tissues have“matched margins” obtained from noncancerous tissue just adjacent to thetumor. These are termed normal adjacent tissues and are denoted “NAT” inthe results below. The tumor tissue and the “matched margins” areevaluated by two independent pathologists (the surgical pathologists andagain by a pathologists at NDR1 or CHTN). This analysis provides a grosshistopathological assessment of tumor differentiation grade. Moreover,most samples include the original surgical pathology report thatprovides information regarding the clinical stage of the patient. Thesematched margins are taken from the tissue surrounding (i.e. immediatelyproximal) to the zone of surgery (designated “NAT”, for normal adjacenttissue, in Table RR). In addition, RNA and cDNA samples were obtainedfrom various human tissues derived from autopsies performed on elderlypeople or sudden death victims (accidents, etc.). These tissues wereascertained to be free of disease and were purchased from variouscommercial sources such as Clontech (Palo Alto, Calif.), ResearchGenetics, and Invitrogen.

[0436] RNA integrity from all samples is controlled for quality byvisual assessment of agarose gel electropherograms using 28S and 18Sribosomal RNA staining intensity ratio as a guide (2:1 to 2.5:1 28s:18s)and the absence of low molecular weight RNAs that would be indicative ofdegradation products. Samples are controlled against genomic DNAcontamination by RTQ PCR reactions run in the absence of reversetranscriptase using probe and primer sets designed to amplify across thespan of a single exon.

[0437] Panel 3D

[0438] The plates of Panel 3D are comprised of 94 cDNA samples and twocontrol samples. Specifically, 92 of these samples are derived fromcultured human cancer cell lines, 2 samples of human primary cerebellartissue and 2 controls. The human cell lines are generally obtained fromATCC (American Type Culture Collection, Manassas, Va.), National CancerInstitute or the German tumor cell bank and fall into the followingtissue groups: Squamous cell carcinoma of the tongue, breast cancer,prostate cancer, melanoma, epidermoid carcinoma, sarcomas, bladdercarcinomas, pancreatic cancers, kidney cancers, leukemias/lymphomas,ovarian/uterine/cervical, gastric, colon, lung and CNS cancer celllines. In addition, there are two independent samples of cerebellum.These cells are all cultured under standard recommended conditions andRNA extracted using the standard procedures. The cell lines in panel 3Dand 1.3D are of the most common cell lines used in the scientificliterature.

[0439] RNA integrity from all samples is controlled for quality byvisual assessment of agarose gel electropherograms using 28S and 18Sribosomal RNA staining intensity ratio as a guide (2:1 to 2.5:1 28s:18s) and the absence of low molecular weight RNAs that would beindicative of degradation products. Samples are controlled againstgenomic DNA contamination by RTQ PCR reactions run in the absence ofreverse transcriptase using probe and primer sets designed to amplifyacross the span of a single exon.

[0440] Panel 4

[0441] Panel 4 includes samples on a 96 well plate (2 control wells, 94test samples) composed of RNA (Panel 4r) or cDNA (Panel 4d) isolatedfrom various human cell lines or tissues related to inflammatoryconditions. Total RNA from control normal tissues such as colon and lung(Stratagene, La Jolla, Calif.) and thymus and kidney (Clontech) wereemployed. Total RNA from liver tissue from cirrhosis patients and kidneyfrom lupus patients was obtained from BioChain (Biochain Institute,Inc., Hayward, Calif.). Intestinal tissue for RNA preparation frompatients diagnosed as having Crohn's disease and ulcerative colitis wasobtained from the National Disease Research Interchange (NDR1)(Philadelphia, Pa.).

[0442] Astrocytes, lung fibroblasts, dermal fibroblasts, coronary arterysmooth muscle cells, small airway epithelium, bronchial epithelium,microvascular dermal endothelial cells, microvascular lung endothelialcells, human pulmonary aortic endothelial cells, human umbilical veinendothelial cells were all purchased from Clonetics (Walkersville, Md.)and grown in the media supplied for these cell types by Clonetics. Theseprimary cell types were activated with various cytokines or combinationsof cytokines for 6 and/or 12-14 hours, as indicated. The followingcytokines were used; IL-1 beta at approximately 1-5 ng/ml, TNF alpha atapproximately 5-10 ng/ml, IFN gamma at approximately 20-50 ng/ml, IL-4at approximately 5-10 ng/ml, IL-9 at approximately 5-10 ng/ml, IL-13 atapproximately 5-10 ng/ml. Endothelial cells were sometimes starved forvarious times by culture in the basal media from Clonetics with 0.1%serum.

[0443] Mononuclear cells were prepared from blood of employees atCuraGen Corporation, using Ficoll. LAK cells were prepared from thesecells by culture in DMEM 5% FCS (Hyclone), 100 μM non essential aminoacids (Gibco/Life Technologies, Rockville, Md.), 1 mM sodium pyruvate(Gibco), mercaptoethanol 5.5×10⁻⁵ M (Gibco), and 10 mM Hepes (Gibco) andInterleukin 2 for 4-6 days. Cells were then either activated with 10-20ng/ml PMA and 1-2 μg/ml ionomycin, IL-12 at 5-10 ng/ml, IFN gamma at20-50 ng/ml and IL-18 at 5-10 ng/ml for 6 hours. In some cases,mononuclear cells were cultured for 4-5 days in DMEM 5% FCS (Hyclone),100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco),mercaptoethanol 5.5×10⁻⁵ M (Gibco), and 10 mM Hepes (Gibco) with PHA(phytohemagglutinin) or PWM (pokeweed mitogen) at approximately 5 μg/ml.Samples were taken at 24, 48 and 72 hours for RNA preparation. MLR(mixed lymphocyte reaction) samples were obtained by taking blood fromtwo donors, isolating the mononuclear cells using Ficoll and mixing theisolated mononuclear cells 1:1 at a final concentration of approximately2×10⁶ cells/ml in DMEM 5% FCS (Hyclone), 100 μM non essential aminoacids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol (5.5×10⁻⁵M) (Gibco), and 10 mM Hepes (Gibco). The MLR was cultured and samplestaken at various time points ranging from 1-7 days for RNA preparation.

[0444] Monocytes were isolated from mononuclear cells using CD14Miltenyi Beads, +ve VS selection columns and a Vario Magnet according tothe manufacturer's instructions. Monocytes were differentiated intodendritic cells by culture in DMEM 5% fetal calf serum (FCS) (Hyclone,Logan, Utah), 100 μM non essential amino acids (Gibco), 1 mM sodiumpyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵ M (Gibco), and 10 mM Hepes(Gibco), 50 ng/ml GMCSF and 5 ng/ml IL-4 for 5-7 days. Macrophages wereprepared by culture of monocytes for 5-7 days in DMEM 5% FCS (Hyclone),100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco),mercaptoethanol 5.5×10⁻⁵ M (Gibco), 10 mM Hepes (Gibco) and 10% AB HumanSerum or MCSF at approximately 50 ng/ml. Monocytes, macrophages anddendritic cells were stimulated for 6 and 12-14 hours withlipopolysaccharide (LPS) at 100 ng/ml. Dendritic cells were alsostimulated with anti-CD40 monoclonal antibody (Pharmingen) at 10,g/mlfor 6 and 12-14 hours.

[0445] CD4 lymphocytes, CD8 lymphocytes and NK cells were also isolatedfrom mononuclear cells using CD4, CD8 and CD56 Miltenyi beads, positiveVS selection columns and a Vario Magnet according to the manufacturer'sinstructions. CD45RA and CD45RO CD4 lymphocytes were isolated bydepleting mononuclear cells of CD8, CD56, CD14 and CD19 cells using CD8,CD56, CD14 and CD19 Miltenyi beads and positive selection. Then CD45RObeads were used to isolate the CD45RO CD4 lymphocytes with the remainingcells being CD45RA CD4 lymphocytes. CD45RA CD4, CD45RO CD4 and CD8lymphocytes were placed in DMEM 5% FCS (Hyclone), 100 μM non essentialamino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol5.5×10⁻⁵ M (Gibco), and 10 mM Hepes (Gibco) and plated at 10⁶ cells/mlonto Falcon 6 well tissue culture plates that had been coated overnightwith 0.5 μg/ml anti-CD28 (Pharmingen) and 3 μg/ml anti-CD3 (OKT3, ATCC)in PBS. After 6 and 24 hours, the cells were harvested for RNApreparation. To prepare chronically activated CD8 lymphocytes, weactivated the isolated CD8 lymphocytes for 4 days on anti-CD28 andanti-CD3 coated plates and then harvested the cells and expanded them inDMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mMsodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵ M (Gibco), and 10 mMHepes (Gibco) and IL-2. The expanded CD8 cells were then activated againwith plate bound anti-CD3 and anti-CD28 for 4 days and expanded asbefore. RNA was isolated 6 and 24 hours after the second activation andafter 4 days of the second expansion culture. The isolated NK cells werecultured in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids(Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵ M(Gibco), and 10 mM Hepes (Gibco) and IL-2 for 4-6 days before RNA wasprepared.

[0446] To obtain B cells, tonsils were procured from NDR1. The tonsilwas cut up with sterile dissecting scissors and then passed through asieve. Tonsil cells were then spun down and resupended at 10⁶ cells/mlin DMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mMsodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵ M (Gibco), and 10 mMHepes (Gibco). To activate the cells, we used PWM at 5 μg/ml oranti-CD40 (Pharmingen) at approximately 10 μg/ml and IL-4 at 5-10 ng/ml.Cells were harvested for RNA preparation at 24,48 and 72 hours.

[0447] To prepare the primary and secondary Th1/Th2 and Tr1 cells,six-well Falcon plates were coated overnight with 10/Ag/ml anti-CD28(Pharmingen) and 2 μg/ml OKT3 (ATCC), and then washed twice with PBS.Umbilical cord blood CD4 lymphocytes (Poietic Systems, German Town, Md.)were cultured at 10⁵-10⁶ cells/ml in DMEM 5% FCS (Hyclone), 100 μM nonessential amino acids (Gibco), 1 mM sodium pyruvate (Gibco),mercaptoethanol 5.5×10⁻⁵ M (Gibco), 10 mM Hepes (Gibco) and IL-2 (4ng/ml). IL-12 (5 ng/ml) and anti-IL4 (1 □g/ml) were used to direct toTh1, while IL-4 (5 ng/ml) and anti-WN gamma (1 □g/ml) were used todirect to Th2 and IL-10 at 5 ng/ml was used to direct to Tr1. After 4-5days, the activated Th1, Th2 and Tr1 lymphocytes were washed once inDMEM and expanded for 4-7 days in DMEM 5% FCS (Hyclone), 100 μM nonessential amino acids (Gibco), 1 mM sodium pyruvate (Gibco),mercaptoethanol 5.5×10⁻⁵ M (Gibco), 10 mM Hepes (Gibco) and IL-2 (1ng/ml). Following this, the activated Th1, Th2 and Tr1 lymphocytes werere-stimulated for 5 days with anti-CD28/OKT3 and cytokines as describedabove, but with the addition of anti-CD95L (1 □g/ml) to preventapoptosis. After 4-5 days, the Th1, Th2 and Tr1 lymphocytes were washedand then expanded again with IL-2 for 4-7 days. Activated Th1 and Th2lymphocytes were maintained in this way for a maximum of three cycles.RNA was prepared from primary and secondary Th1, Th2 and Tr1 after 6 and24 hours following the second and third activations with plate boundanti-CD3 and anti-CD28 mAbs and 4 days into the second and thirdexpansion cultures in Interleukin 2.

[0448] The following leukocyte cells lines were obtained from the ATCC:Ramos, EOL-1, KU-812. EOL cells were further differentiated by culturein 0.1 mM dbcAMP at 5×10⁵ cells/ml for 8 days, changing the media every3 days and adjusting the cell concentration to 5×10⁵ cells/ml. For theculture of these cells, we used DMEM or RPMI (as recommended by theATCC), with the addition of 5% FCS (Hyclone), 100,uM non essential aminoacids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵ M(Gibco), 10 mM Hepes (Gibco). RNA was either prepared from resting cellsor cells activated with PMA at 10 ng/ml and ionomycin at 1 μg/ml for 6and 14 hours. Keratinocyte line CCD106 and an airway epithelial tumorline NCI-H292 were also obtained from the ATCC. Both were cultured inDMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mMsodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵ M (Gibco), and 10 mMHepes (Gibco). CCD1106 cells were activated for 6 and 14 hours withapproximately 5 ng/ml TNF alpha and 1 ng/ml IL-1 beta, while NC1-H292cells were activated for 6 and 14 hours with the following cytokines: 5ng/ml IL-4, 5 ng/ml IL-9, 5 ng/ml IL-13 and 25 ng/ml IFN gamma.

[0449] For these cell lines and blood cells, RNA was prepared by lysingapproximately 10⁷ cells/ml using Trizol (Gibco BRL). Briefly, {fraction(1/10)} volume of bromochloropropane (Molecular Research Corporation)was added to the RNA sample, vortexed and after 10 minutes at roomtemperature, the tubes were spun at 14,000 rpm in a Sorvall SS34 rotor.The aqueous phase was removed and placed in a 15 ml Falcon Tube. Anequal volume of isopropanol was added and left at −20 degrees C.overnight. The precipitated RNA was spun down at 9,000 rpm for 15 min ina Sorvall SS34 rotor and washed in 70% ethanol. The pellet wasredissolved in 300 μl of RNAse-free water and 35 μl buffer (Promega) 5μl DTT, 7 μl RNAsin and 8,ul DNAse were added. The tube was incubated at37 degrees C. for 30 minutes to remove contaminating genomic DNA,extracted once with phenol chloroform and re-precipitated with {fraction(1/10)} volume of 3 M sodium acetate and 2 volumes of 100% ethanol. TheRNA was spun down and placed in RNAse free water. RNA was stored at −80degrees C.

[0450] Panel CNSD.01

[0451] The plates for Panel CNSD.01 include two control wells and 94test samples comprised of cDNA isolated from postmortem human braintissue obtained from the Harvard Brain Tissue Resource Center. Brainsare removed from calvaria of donors between 4 and 24 hours after death,sectioned by neuroanatomists, and frozen at −80° C. in liquid nitrogenvapor. All brains are sectioned and examined by neuropathologists toconfirm diagnoses with clear associated neuropathology.

[0452] Disease diagnoses are taken from patient records. The panelcontains two brains from each of the following diagnoses: Alzheimer'sdisease, Parkinson's disease, Huntington's disease, ProgressiveSupernuclear Palsy, Depression, and “Normal controls”. Within each ofthese brains, the following regions are represented: cingulate gyrus,temporal pole, globus palladus, substantia nigra, Brodman Area 4(primary motor strip), Brodman Area 7 (parietal cortex), Brodman Area 9(prefrontal cortex), and Brodman area 17 (occipital cortex). Not allbrain regions are represented in all cases; e.g., Huntington's diseaseis characterized in part by neurodegeneration in the globus palladus,thus this region is impossible to obtain from confirmed Huntington'scases. Likewise Parkinson's disease is characterized by degeneration ofthe substantia nigra making this region more difficult to obtain. Normalcontrol brains were examined for neuropathology and found to be free ofany pathology consistent with neurodegeneration.

[0453] RNA integrity from all samples is controlled for quality byvisual assessment of agarose gel electropherograms using 28S and 18Sribosomal RNA staining intensity ratio as a guide (2:1 to 2.5:1 28s:18s)and the absence of low molecular weight RNAs that would be indicative ofdegradation products. Samples are controlled against genomic DNAcontamination by RTQ PCR reactions run in the absence of reversetranscriptase using probe and primer sets designed to amplify across thespan of a single exon.

[0454] In the labels employed to identify tissues in the CNS panel, thefollowing abbreviations are used:

[0455] PSP=Progressive supranuclear palsy

[0456] Sub Nigra=Substantia nigra

[0457] Glob Palladus=Globus palladus

[0458] Temp Pole=Temporal pole

[0459] Cing Gyr=Cingulate gyrus

[0460] BA 4=Brodman Area 4

[0461] A. MOL1a

[0462] Expression of gene SC29674552_EXT was assessed using theprimer-probe sets Ag267 and Ag1308, described in Tables 10 and 11.Results of the RTQ-PCR runs are shown in Tables 12, 13, 14, 15, and 16TABLE 10 Probe Name Ag267 Start SEQ ID Primers Sequences TM LengthPosition NO: Forward 5′-TGCAGCGACCATCGTTCA-3′ 18 50 65 Probe TET-5′- 3276 66 CTGCTGTAACATTCATCAATCTGGTCACTGCA-3′- TAMRA REVERSE5′-GGGTACATGGGCGCCAT-3′ 17 109 67

[0463] TABLE 11 Probe Name: Ag1308 Start SEQ ID Primers Sequences TMLength Position NO: Forward 5′-GAGTGTGACATTCCAGGACACT-3′ 59.1 22 139 68Probe FAM-5′-ATGGTGGCACCTGCCTCAACCTG-3′- 71.6 23 167 69 TAMRA Reverse5′-GCACTGGCACTGGTAGGAA-3′ 59.8 19 195 70

[0464] TABLE 12 Panel 1 Relative Relative Expression (%) Expression (%)Tissue Name 1tm420t_ag267 Tissue Name 1tm420t_ag267 Endothelial cells4.4 Kidney (fetal) 19.8 Endothelial cells (treated) 5.3 Renal ca. 786-017.4 Pancreas 11.5 Renal ca. A498 20.6 Pancreatic ca. CAPAN 2 7.0 Renalca. RXF 393 18.4 Adipose 40.3 Renal ca. ACHN 20.4 Adrenal gland 5.8Renal ca. UO-31 20.3 Thyroid 11.5 Renal ca. TK-10 100.0 Salivary gland7.5 Liver 7.3 Pituitary gland 4.9 Liver (fetal) 2.3 Brain (fetal) 1.2Liver ca. (hepatoblast) HepG2 0.0 Brain (whole) 7.9 Lung 5.4 Brain(amygdala) 5.3 Lung (fetal) 4.2 Brain (cerebellum) 16.6 Lung ca. (smallcell) LX-1 2.8 Brain (hippocampus) 1.8 Lung ca. (small cell) NCI-H69 5.5Brain (substantia nigra) 2.0 Lung ca. (s. cell var.) SHP-77 3.2 Brain(thalamus) 1.6 Lung ca. (large cell) NCI-H460 6.7 Brain (hypothalamus)0.9 Lung ca. (non-sm. cell) A549 6.5 Spinal cord 3.0 Lung ca. (non-s.cell) NCI-H23 9.0 CNS ca. (glio/astro) U87-MG 70.7 Lung ca (non-s. cell)HOP-62 14.4 CNS ca. (glio/astro) U-118-MG 21.6 Lung ca. (non-s. cl)NCI-H522 56.6 CNS ca. (astro) SW1783 20.7 Lung ca. (squam.) SW 900 28.1CNS ca.* (neuro; met) SK-N- 0.0 Lung ca. (squam.) NCI-H596 2.9 AS CNSca. (astro) SF-539 14.6 Mammary gland 35.1 CNS ca. (astro) SNB-75 15.8Breast ca.* (pl. effusion) MCF-7 32.3 CNS ca. (glio) SNB-19 62.8 Breastca.* (pl. ef) MDA-MB- 19.6 231 CNS ca. (glio) U251 5.9 Breast ca.* (pl.effusion) T47D 19.1 CNS ca. (glio) SF-295 23.0 Breast ca. BT-549 11.0Heart 5.7 Breast ca. MDA-N 7.9 Skeletal muscle 1.3 Ovary 44.4 Bonemarrow 4.1 Ovarian ca. OVCAR-3 15.9 Thymus 32.3 Ovarian ca. OVCAR-4 44.4Spleen 3.4 Ovarian ca. OVCAR-5 30.1 Lymph node 5.0 Ovarian ca. OVCAR-850.7 Colon (ascending) 16.8 Ovarian ca. IGROV-1 10.4 Stomach 11.1Ovarian ca.* (ascites) SK-OV-3 11.9 Small intestine 2.6 Uterus 8.3 Colonca. SW480 6.2 Placenta 21.0 Colon ca.* (SW480 met) SW620 0.9 Prostate11.3 Colon ca. HT29 6.2 Prostate ca.* (bone met)PC-3 22.2 Colon ca.HCT-116 19.2 Testis 92.0 Colon ca. CaCo-2 15.0 Melanoma Hs688(A).T 13.5Colon ca. HCT-15 20.2 Melanoma* (met) Hs688(B).T 20.3 Colon ca. HCC-29983.9 Melanoma UACC-62 8.5 Gastric ca.* (liver met) NCI- 22.8 Melanoma M1415.2 N87 Bladder 13.3 Melanoma LOX IMVI 54.7 Trachea 10.3 Melanoma*(met) SK-MEL-5 6.8 Kidney 6.4 Melanoma SK-MEL-28 38.4

[0465] TABLE 13 Panel 1.2 Relative Relative Expression (%) Expression(%) Tissue Name 1.2tm1287t_ag267 Tissue Name 1.2tm1287t_ag267Endothelial cells 8.2 Renal ca. 786-0 16.8 Endothelial cells (treated)15.0 Renal ca. A498 32.5 Pancreas 1.4 Renal ca. RXF 393 15.6 Pancreaticca. CAPAN 2 2.9 Renal ca. ACHN 15.3 Adrenal Gland (new lot*) 14.7 Renalca. UO-31 15.9 Thyroid 2.1 Renal ca. TK-10 53.2 Salivary gland 14.8Liver 7.7 Pituitary gland 3.2 Liver (fetal) 3.8 Brain (fetal) 1.9 Liverca. (hepatoblast) HepG2 0.0 Brain (whole) 7.1 Lung 6.0 Brain (amygdala)7.7 Lung (fetal) 3.6 Brain (cerebellum) 5.0 Lung ca. (small cell) LX-12.0 Brain (hippocampus) 8.7 Lung ca. (small cell) NCI-H69 4.5 Brain(thalamus) 1.5 Lung ca. (s. cell var.) SHP-77 0.3 Cerebral Cortex 52.8Lung ca. (large cell) NCI-H460 14.8 Spinal cord 6.4 Lung ca. (non-sm.cell) A549 8.3 CNS ca. (glio/astro) U87-MG 100.0 Lung ca. (non-s. cell)NCI-H23 13.4 CNS ca. (glio/astro) U-118-MG 37.1 Lung ca (non-s. cell)HOP-62 30.4 CNS ca. (astro) SW1783 14.2 Lung ca. (non-s. cl) NCI-H52257.4 CNS ca.* (neuro; met) SK-N-AS 0.1 Lung ca. (squam.) SW 900 20.9 CNSca. (astro) SF-539 11.9 Lung ca. (squam.) NCI-H596 2.7 CNS ca. (astro)SNB-75 9.6 Mammary gland 13.3 CNS ca. (glio) SNB-19 80.7 Breast ca.*(pl. effusion) MCF-7 31.9 CNS ca. (glio) U251 26.6 Breast ca.* (pl. ef)MDA-MB-231 23.7 CNS ca. (glio) SF-295 6.6 Breast ca.* (pl. effusion)T47D 12.2 Heart 21.0 Breast ca. BT-549 11.7 Skeletal Muscle (new lot*)4.9 Breast ca. MDA-N 12.2 Bone marrow 2.2 Ovary 34.2 Thymus 2.1 Ovarianca. OVCAR-3 35.8 Spleen 2.7 Ovarian ca. OVCAR-4 32.3 Lymph node 9.9Ovarian ca. OVCAR-5 21.0 Colorectal 8.8 Ovarian ca. OVCAR-8 32.5 Stomach8.7 Ovarian ca. IGROV-1 20.0 Small intestine 4.2 Ovarian ca.* (ascites)SK-OV-3 22.2 Colon ca. SW480 2.5 Uterus 5.2 Colon ca.* (SW480 met) SW6200.5 Placenta 24.3 Colon ca. HT29 1.4 Prostate 9.2 Colon ca. HCT-116 13.4Prostate ca.* (bone met) PC-3 30.6 Colon ca. CaCo-2 7.5 Testis 8.7 83219CC Well to Mod Diff 6.9 Melanoma Hs688(A).T 10.4 (ODO3866) Colon ca.HCC-2998 14.7 Melanoma* (met) Hs688(B).T 15.8 Gastric ca.* (liver met)38.2 Melanoma UACC-62 27.0 NCI-N87 Bladder 37.1 Melanoma M14 13.1Trachea 3.5 Melanoma LOX IMVI 8.4 Kidney 7.3 Melanoma* (met) SK-MEL-512.9 Kidney (fetal) 29.5 Adipose 27.5

[0466] TABLE 14 Panel 2D Relative Relative Expression (%) Expression (%)Tissue Name 2Dtm2336t_ag267 Tissue Name 2Dtm2336t_ag267 Normal ColonGENPAK 23.7 Kidney NAT Clontech 7.7 061003 8120608 83219 CC Well to ModDiff 6.1 Kidney Cancer Clontech 0.7 (ODO3866) 8120613 83220 CC NAT(ODO3866) 8.2 Kidney NAT Clontech 10.2 8120614 83221 CC Gr. 2rectosigmoid 3.8 Kidney Cancer Clontech 24.0 (ODO3868) 9010320 83222 CCNAT (ODO3868) 3.5 Kidney NAT Clontech 24.3 9010321 83235 CC Mod Diff 3.7Normal Uterus GENPAK 8.4 (ODO3920) 061018 83236 CC NAT (ODO3920) 6.4Uterus Cancer GENPAK 15.5 064011 83237 CC Gr. 2 ascend colon 7.5 NormalThyroid Clontech A + 11.0 (ODO3921) 6570-1 83238 CC NAT (ODO3921) 4.0Thyroid Cancer GENPAK 27.9 064010 83241 CC from Partial 7.6 ThyroidCancer INVITROGEN 14.0 Hepatectomy (ODO4309) A302152 83242 Liver NAT(ODO4309) 7.5 Thyroid NAT INVITROGEN 21.6 A302153 87472 Colon mets tolung 6.0 Normal Breast GENPAK 33.7 (ODO4451-01) 061019 87473 Lung NAT(ODO4451- 8.4 84877 Breast Cancer 11.9 02) ODO4566) Normal ProstateClontech A + 7.7 85975 Breast Cancer 18.3 6546-1 (ODO4590-01 84140Prostate Cancer 22.1 85976 Breast Cancer Mets 37.1 (OD04410) (ODO4590-0384141 Prostate NAT 19.8 87070 Breast Cancer 31.4 (OD04410) Metastasis(OD04655-05) 87073 Prostate Cancer 12.5 GENPAK Breast Cancer 15.2(OD04720-01) 064006 87074 Prostate NAT 27.5 Breast Cancer Res. Gen. 102430.8 (OD04720-02) Normal Lung GENPAK 21.5 Breast Cancer Clontech 100.0061010 9100266 83239 Lung Met to Muscle 10.2 Breast NAT Clontech 910026545.4 (ODO4286) 83240 Muscle NAT 10.2 Breast Cancer INVITROGEN 29.3(ODO4286) A209073 84136 Lung Malignant Cancer 16.0 Breast NAT INVITROGEN26.1 (OD03126) A2090734 84137 Lung NAT (OD03126) 15.9 Normal LiverGENPAK 6.1 061009 84871 Lung Cancer (OD04404) 8.0 Liver Cancer GENPAK064003 11.7 84872 Lung NAT (OD04404) 19.2 Liver Cancer Research 6.4Genetics RNA 1025 6.4 84875 Lung Cancer (OD04565) 3.4 Liver CancerResearch 10.6 Genetics RNA 1026 84876 Lung NAT (OD04565) 8.4 PairedLiver Cancer Tissue 14.7 Research Genetics RNA 6004-T 85950 Lung Cancer(OD04237-01) 27.4 Paired Liver Tissue Research 4.4 Genetics RNA 6004-N85970 Lung NAT (ODO4237-02) 15.8 Paired Liver Cancer Tissue 11.5Research Genetics RNA 6005-T 83255 Ocular Mel Met to Liver 11.0 PairedLiver Tissue Research 5.4 (ODO4310) Genetics RNA 6005-N 83256 LiverNAT(ODO4310) 7.0 Normal Bladder GENPAK 19.5 061001 84139 Melanoma Metsto Lung 12.1 Bladder Cancer Research 9.3 (OD04321) Genetics RNA 102384138 Lung NAT (OD04321) 23.5 Bladder Cancer INVITROGEN 14.7 A302173Normal Kidney GENPAK 25.2 87071 Bladder Cancer 13.3 061008 (OD04718-01)83786 Kidney Ca. Nuclear 24.1 87072 Bladder Normal 17.3 grade 2(OD04338) Adjacent (OD04718-03) 83787 Kidney NAT (OD04338) 7.7 NormalOvary Res. Gen. 14.5 83788 Kidney Ca Nuclear 14.5 Ovarian Cancer GENPAK26.8 grade 1/2 (OD04339) 064008 83789 Kidney NAT (OD04339) 9.2 87492Ovary Cancer 15.5 (OD04768-07) 83790 Kidney Ca, Clear cell 19.9 87493Ovary NAT (OD04768-08) 9.9 type (OD04340) 83791 Kidney NAT (OD04340)15.3 Normal Stomach GENPAK 6.3 061017 83792 Kidney Ca, Nuclear 14.6Gastric Cancer Clontech 3.7 grade 3 (OD04348) 9060358 83793 Kidney NAT(OD04348) 14.3 NAT Stomach Clontech 5.0 9060359 87474 Kidney Cancer 19.3Gastric Cancer Clontech 11.8 (OD04622-01) 9060395 87475 Kidney NAT(OD04622-03) 5.3 NAT Stomach Clontech 5.9 9060394 85973 Kidney Cancer17.2 Gastric Cancer Clontech 14.5 (OD04450-01) 9060397 85974 Kidney NAT(OD04450-03) 10.4 NAT Stomach Clontech 2.8 9060396 Kidney CancerClontech 17.9 Gastric Cancer GENPAK 5.7 8120607 064005

[0467] TABLE 15 Panel 2.2 Relative Relative Expression (%) Expression(%) Tissue Name 2.2x4tm6515f_ag1308_b2 Tissue Name2.2x4tm6515f_ag1308_b2 Normal Colon GENPAK 26.3 83793 Kidney NAT(OD04348) 83.7 061003 97759 Colon cancer (OD06064) 20.5 98938 Kidneymalignant cancer 9.7 (OD06204B) 97760 Colon cancer NAT 6.5 98939 Kidneynormal adjacent 15.3 (OD06064) tissue (OD06204E) 97778 Colon cancer(OD06159) 2.6 85973 Kidney Cancer 55.1 (OD04450-01) 97779 Colon cancerNAT 17.2 85974 Kidney NAT (OD04450-03) 23.4 (OD06159) 98861 Colon cancer(OD06297-04) 2.7 Kidney Cancer Clontech 2.1 8120613 98862 Colon cancerNAT 25.9 Kidney NAT Clontech 8120614 12.5 (OD06297-015) 83237 CC Gr. 2ascend colon 9.2 Kidney Cancer Clontech 12.6 (ODO3921) 9010320 83238CCNAT (ODO3921) 11.3 Kidney NAT Clontech 9010321 7.0 97766 Colon cancermetastasis 5.4 Kidney Cancer Clontech 19.0 (OD06104) 8120607 97767 LungNAT (OD06104) 4.6 Kidney NAT Clontech 8120608 6.5 87472 Colon mets tolung 22.6 Normal Uterus GENPAK 31.5 (OD04451-01) 061018 87473 Lung NAT(OD04451-02) 18.3 Uterus Cancer GENPAK 21.4 064011 Normal ProstateClontech A + 7.2 Normal Thyroid Clontech A + 1.2 6546-1 (8090438) 6570-1(7080817) 84140 Prostate Cancer 11.0 Thyroid Cancer GENPAK 16.7(OD04410) 064010 84141 Prostate NAT 20.3 Thyroid Cancer INVITROGEN 44.5(OD04410) A302152 Normal Ovary Res. Gen. 29.1 Thyroid NAT INVITROGEN14.0 A302153 98863 Ovarian cancer 31.5 Normal Breast GENPAK 39.9(OD06283-03) 061019 98865 Ovarian cancer 19.3 84877 Breast Cancer 11.0NAT/fallopian tube (OD06283-07) (OD04566 Ovarian Cancer GENPAK 22.2Breast Cancer Res. Gen. 1024 49.2 064008 97773 Ovarian cancer 12.4 85975Breast Cancer 50.8 (OD06145) (OD04590-01) 97775 Ovarian cancer NAT 36.285976 Breast Cancer Mets 42.9 (OD06145) (OD04590-03) 98853 Ovariancancer 9.3 87070 Breast Cancer Metastasis 72.1 (OD06455-03) (OD04655-05)98854 Ovarian NAT 7.6 GENPAK Breast Cancer 29.0 (OD06455-07) Fallopiantube 064006 Normal Lung GENPAK 061010 25.4 Breast Cancer Clontech 41.19100266 92337 Invasive poor diff. lung 10.9 Breast NAT Clontech 910026515.6 adeno (ODO4945-01 92338 Lung NAT (ODO4945-03) 20.2 Breast CancerINVITROGEN 13.5 A209073 84136 Lung Malignant Cancer 10.5 Breast NATINVITROGEN 43.8 (OD03126) A2090734 84137 Lung NAT (OD03126) 24.5 97763Breast cancer 49.6 (OD06083) 90372 Lung Cancer 25.9 97764 Breast cancernode 44.3 (OD05014A) metastasis (OD06083) 90373 Lung NAT (OD05014B) 26.1Normal Liver GENPAK 38.6 061009 97761 Lung cancer (OD06081) 8.3 LiverCancer Research Genetics 13.2 RNA 1026 97762 Lung cancer NAT 19.4 LiverCancer Research Genetics 36.4 (OD06081) RNA 1025 85950 Lung Cancer(OD04237-01) 13.3 Paired Liver Cancer Tissue 23.8 Research Genetics RNA6004-T 85970 Lung NAT (OD04237-02) 41.6 Paired Liver Tissue Research 5.9Genetics RNA 6004-N 83255 Ocular Mel Met to Liver 12.9 Paired LiverCancer Tissue 25.1 (ODO4310) Research Genetics RNA 6005-T 83256 LiverNAT (ODO4310) 11.5 Paired Liver Tissue Research 47.4 Genetics RNA 6005-N84139 Melanoma Mets to Lung 22.9 Liver Cancer GENPAK 064003 36.9(OD04321) 84138 Lung NAT (OD04321) 13.6 Normal Bladder GENPAK 18.9061001 Normal Kidney GENPAK 19.9 Bladder Cancer Research 9.6 061008Genetics RNA 1023 83786 Kidney Ca, Nuclear 59.8 Bladder CancerINVITROGEN 24.5 grade 2 (OD04338) A302173 83787 Kidney NAT (OD04338)23.8 Normal Stomach GENPAK 43.1 061017 83788 Kidney Ca Nuclear grade100.00 Gastric Cancer Clontech 6.2 1/2 (OD04339) 9060397 83789 KidneyNAT (OD04339) 7.3 NAT Stomach Clontech 7.3 9060396 83790 Kidney Ca,Clear cell 15.0 Gastric Cancer Clontech 9.3 type (OD04340) 9060395 83791Kidney NAT (OD04340) 22.5 NAT Stomach Clontech 13.3 9060394 83792 KidneyCa, Nuclear 14.3 Gastric Cancer GENPAK 9.4 grade 3 (OD04348) 064005

[0468] TABLE 16 Panel 4D Relative Relative Expression (%) Expression (%)Tissue Name 4Dtm1935t_ag267 4Dtm1888f_ag1308 93768_SecondaryTh1_anti-CD28/anti-CD3 51.0 23.2 93769_Secondary Th2_anti-CD28/anti-CD343.5 24.1 93770_Secondary Tr1_anti-CD28/anti-CD3 42.6 23.893573_Secondary Th1_resting day 4-6 in IL-2 11.7 7.4 93572_SecondaryTh2_resting day 4-6 in IL-2 21.9 12.4 93571_Secondary Tr1_resting day4-6 in IL-2 12.1 8.0 93568_primary Th1_anti-CD28/anti-CD3 47.0 29.593569_primary Th2_anti-CD28/anti-CD3 28.1 22.8 93570_primaryTr1_anti-CD28/anti-CD3 45.1 37.9 93565_primary Th1_resting dy 4-6 inIL-2 51.8 49.3 93566_primary Th2_resting dy 4-6 in IL-2 23.0 27.993567_primary Tr1_resting dy 4-6 in IL-2 34.2 27.4 93351_CD45RA CD4lymphocyte_anti-CD28/anti-CD3 32.3 16.5 93352_CD45RO CD4lymphocyte_anti-CD28/anti-CD3 52.5 29.3 93251_CD8Lymphocytes_anti-CD28/anti-CD3 22.8 14.9 93353_chronic CD8 Lymphocytes2ry_resting dy 4-6 in IL-2 20.2 12.6 93574_chronic CD8 Lymphocytes2ry_activated CD3/CD28 22.1 14.2 93354_CD4_none 6.8 8.0 93252_SecondaryTh1/Th2/Tr1_anti-CD95 CH11 31.0 23.0 93103_LAK cells_resting 62.0 30.893788_LAK cells_IL-2 47.3 27.4 93787_LAK cells_IL-2 + IL-12 41.5 23.393789_LAK cells_IL-2 + IFN gamma 36.1 27.4 93790_LAK cells_IL-2 + IL-1827.0 19.8 93104_LAK cells_PMA/ionomycin and IL-18 38.2 21.2 93578_NKCells IL-2_resting 17.0 14.7 93109_Mixed Lymphohocyte Reaction_Two WayMLR 30.8 27.7 93110_Mixed Lymphocyte Reaction_Two Way MLR 19.6 12.293111_Mixed Lymphocyte Reaction_Two Way MLR 17.3 10.4 93112_MononuclearCells (PBMCs)_resting 23.0 17.2 93113_Mononuclear Cells (PBMCs)_PWM 91.456.6 93114_Mononuclear Cells (PBMCs)_PHA-L 52.5 31.9 93249_Ramos (Bcell)_none 14.6 14.7 93250_Ramos (B cell)_ionomycin 18.2 21.9 93349_Blymphocytes_PWM 43.2 30.6 93350_B lymphoytes_CD40L and IL-4 12.7 11.392665_EOL-1 (Eosinophil)_dbcAMP differentiated 5.4 5.7 93248_EOL-1(Eosinophil)_dbcAMP/PMAionomycin 14.2 12.9 93356_Dendritic Cells_none28.5 16.2 93355_Dendritic Cells_LPS 100 ng/ml 23.0 14.7 93775_DendriticCells_anti-CD40 21.5 12.3 93774_Monocytes_resting 81.8 58.293776_Monocytes_LPS 50 ng/ml 100.0 100.0 93581_Macrophages_resting 75.333.4 93582_Macrophages_LPS 100 ng/ml 54.3 30.8 93098_HUVEC(Endothelial)_none 12.7 6.3 93099_HUVEC (Endothelial)_starved 18.3 12.793100_HUVEC (Endothelial)_IL-1b 6.9 4.9 93779_HUVEC (Endothelial)_IFNgamma 11.7 6.9 93102_HUVEC (Endothelial)_TNF alpha + IFN gamma 12.9 6.493101_HUVEC (Endothelial)_TNF alpha + IL4 20.7 10.7 93781_HUVEC(Endothelial)_IL-11 4.8 2.8 93583_Lung Microvascular EndothelialCells_none 14.8 7.4 93584_Lung Microvascular Endothelial Cells_TNFa (4ng/ml) 25.3 9.8 and IL1b (1 ng/ml) 92662_Microvascular Dermalendothelium_none 27.4 16.4 92663_Microsvasular Dermal endothelium_TNFa(4 ng/ml) and 40.3 17.8 IL1b (1 ng/ml) 93773_Bronchial epithelium_TNFa(4 ng/ml) and IL1b (1 37.6 24.1 ng/ml)** 93347_Small AirwayEpithelium_none 11.6 7.3 93348_Small Airway Epithelium_TNFa (4 ng/ml)and IL1b (1 81.8 53.2 ng/ml) 92668_Coronery Artery SMC_resting 38.2 24.592669_Coronery Artery SMC_TNFa (4 ng/ml) and IL1b (1 32.3 24.0 ng/ml)93107_astrocytes_resting 14.7 8.6 93108_astrocytes_TNFa (4 ng/ml) andIL1b (1 ng/ml) 24.7 14.2 92666_KU-812 (Basophil)_resting 12.4 9.992667_KU-812 (Basophil)_PMA/ionoycin 46.7 29.3 93579_CCD1106(Keratinocytes)_none 13.7 8.9 93580_CCD1106 (Keratinocytes)_TNFa andIFNg** 81.8 57.4 93791_Liver Cirrhosis 5.4 4.3 93792_Lupus Kidney 6.66.4 93577_NCI-H292 32.8 27.4 93358_NCI-H292_IL-4 41.8 34.993360_NCI-H292_IL-9 33.4 29.7 93359_NCI-H292_IL-13 27.0 21.993357_NCI-H292_IFN gamma 18.6 15.1 93777_HPAEC_ 7.5 4.6 93778_HPAEC_IL-1beta/TNA alpha 26.6 14.5 93254_Normal Human Lung Fibroblast_none 27.012.9 93253_Normal Human Lung Fibroblast_TNFa (4 ng/ml) and IL- 11.7 7.51b (1 ng/ml) 93257_Normal Human Lung Fibroblast_IL-4 31.9 15.993256_Normal Human Lung Fibroblast_IL-9 0.0 12.8 93255_Normal Human LungFibroblast_IL-13 38.7 26.6 93258_Normal Human Lung Fibroblast_IFN gamma52.5 26.1 93106_Dermal Fibroblasts CCD1070_resting 57.0 34.993361_Dermal Fibroblasts CCD1070_TNF alpha 4 ng/ml 87.1 60.793105_Dermal Fibroblasts CCD1070_IL-1 beta 1 ng/ml 46.7 37.493772_dermal fibroblast_IFN gamma 28.9 14.5 93771_dermal fibroblast_IL-451.0 27.7 93259_IBD Colitis 1** 4.9 4.8 93260_IBD Colitis 2 1.1 0.893261_IBD Crohns 1.0 1.0 735010_Colon_normal 12.4 6.7 735019_Lung_none24.7 11.7 64028-1_Thymus_none 33.4 27.5 64030-1_Kidney_none 22.5 20.6

[0469] Panel 1 Summary: Ag267 Among the normal tissues on this panel,highest expression of the MOL1a gene is detected in testis (CT value=25)and adipose. High expression in adipose might suggest that the MOL1agene plays a role in the development of metabolic diseases, such asobesity or diabetes. In addition, expression of this gene is high in arenal cancer cell line (CT value=25). Moderate expression of the MOL1agene is also seen in most regions of normal brain. Strikingly, the MOL1atranscript appears at much higher levels in a number of CNS cancer celllines. Therefore, inhibition of the MOL1a gene product using amonoclonal antibody and/or small molecule therapeutic may be useful forthe treatment of some renal cell and CNS carcinomas.

[0470] Panel 102 Summary: Ag267 Expression of the MOL1a gene is highestin the cerebral cortex (CT value=25) with more moderate expressiondetected in most other regions of normal brain, suggesting a role forthis gene in neurological function. Consistent with the results seen inPanel 1, this gene is strikingly overexpressed in a number of CNS cancercell lines (specifically glioma and astrocytoma). Moderateoverexpression of the MOL1a gene is also detected in renal cell cancerand lung cancer cell lines relative to the normal controls. The MOL1agene product displays moderate similarity to the Notch protein that hasbeen shown to be involved in cell signalling and has been implicated inoncogenesis. Therefore, the MOL1a gene may be a good marker for CNS orother cancers and would potentially serve as a good drug target for thetreatment of certain cancers. This gene is also well expressed inseveral metabolic tissues (specifically adipose, liver and pancreas) andmay thus have application for the treatment of metabolic diseases suchas diabetes and obesity. Of particular interest is the good expression(CT value=30.6) in pancreas. The human pancreas-specific gene SEL-11 isthought to be a negative regulator of the notch receptor (Harada, Y. etal. J Hum Genet 44(5):330-6, 1999). Thus, the notch-like MOL1a gene andnotch receptor may have potential therapeutic use in diseases involvingthe pancreas.

[0471] Panel 1.3D Summary: Ag267 Among normal tissues, highest MOL1atranscript levels are found in adipose (CT value=30). As was seen forPanels 1 and 1.2, moderate expression of this gene is detected in mostregions of normal brain and the gene is strikingly over expressed in anumber of CNS cancer cell lines. In general, expression of the MOL1agene appears to be higher in cell lines when compared to tissue samples.A cluster of expression associated with brain, breast and renal cancercell lines is evident. Thus, the expression of this gene could beassociated with cancer cells when compared to normal, since these celllines are derived from cancers. Alternatively, the expression of thisgene could be associated with cell division, since a high percentage ofcells in culture are actively dividing when compared to cells in tissue.

[0472] Panel 2D Summary: Ag267 Expression of the MOL1a gene in panel 2Dappears to be widespread across most of the samples. However, thereseems to be significant dysregulation in breast cancers when compared tonormal adjacent tissues. Thus, therapeutic modulation of this gene mightshow utility in the treatment of breast cancers.

[0473] Panel 2.2 Summary: Ag1308 The expression of this gene appears tobe widespread across most of the samples in panel 2.2. In a couple ofinstances of renal cell cancer, there seems to be significantdysregulation of the expression of this gene when compared to normaladjacent tissue. Thus, therapeutic modulation of this gene might beuseful in the treatment of a sub-set of renal cancers.

[0474] Panel 4D Summary: Ag267/Ag1308 The MOL1a transcript is broadlyexpressed in fibroblasts, keratinocytes, B cells, and T cells, althoughat a moderate level. High expression of the transcript is also found inmonocytes, whether activated or not. In addition, the transcript isup-regulated (7 fold) in keratinocytes and small airway epitheliun bytreatment with TNFa and IL-1. The Notch-like protein encoded by theMOL1a gene may regulate cell survival based on its homology to otherNotch proteins. Therefore, protein therapeutics (agonist or antagonists)against the MOL1a gene product may be beneficial in the treatment oflung diseases, such as asthma and emphysema, or in the treatment of skindiseases, such as psoriasis and contact sensitivity.

[0475] B. MOL2

[0476] Expression of gene MOL2 was assessed using the primer-probe setAg2120, described in Table 17. Results of the RTQ-PCR runs are shown inTables 18, 19, 20, and 21 TABLE 17 Probe Name Ag2120 Start SEQ IDPrimers Sequences TM Length Position NO: Forward5′-GCTGATTGCAAGAAGATGTTTC-3′ 59 22 103 71 ProbeTET-5′-TTTTGTCAGCCCTGATTTCTTCGACA- 68.8 26 140 72 3′-TAMRA Reverse5′-CCGATATGTCAGAATCTGCATT-3′ 59.1 22 166 73

[0477] TABLE 18 Panel 1.3D Relative Relative Expression (%) Expression(%) Tissue Name 1.3Dtm3025t_ag2120 1.3dtm3058t_ag2120 Liveradenocarcinoma 0.5 0.1 Pancreas 0.3 0.2 Pancreatic ca. CAPAN 2 1.0 1.1Adrenal gland 12.8 10.8 Thyroid 2.1 1.3 Salivary gland 0.6 1.1 Pituitarygland 0.6 0.3 Brain (fetal) 7.9 8.8 Brain (whole) 26.8 23.8 Brain(amygdala) 27.5 17.8 Brain (cerebellum) 17.4 19.2 Brain (hippocampus)64.6 58.6 Brain (substantia nigra) 2.2 3.5 Brain (thalamus) 3.6 3.0Cerebral Cortex 100.0 100.0 Spinal cord 0.5 1.2 CNS ca. (glio/astro)U87-MG 0.8 0.5 CNS ca. (glio/astro) U-118-MG 3.2 4.7 CNS ca. (astro)SW1783 0.7 0.8 CNS ca.* (neuro; met) SK-N-AS 0.4 0.2 CNS ca. (astro)SF-539 0.4 0.3 CNS ca. (astro) SNB-75 0.5 0.2 CNS ca. (glio) SNB-19 0.41.2 CNS ca. (glio) U251 1.6 1.3 CNS ca. (glio) SF-295 1.9 0.8 Heart(fetal) 3.3 2.2 Heart 0.3 0.6 Fetal Skeletal 6.8 9.3 Skeletal muscle 3.44.0 Bone marrow 0.9 1.6 Thymus 0.9 0.5 Spleen 0.4 0.0 Lymph node 1.2 0.6Colorectal 1.6 1.1 Stomach 1.0 0.2 Small intestine 0.2 2.0 Colon ca.SW480 0.8 1.6 Colon ca.* (SW480 met) SW620 0.0 1.4 Colon ca. HT29 0.20.5 Colon ca. HCT-116 0.3 0.2 Colon ca. CaCo-2 0.6 0.0 83219 CC Well toMod Diff(ODO3866) 1.5 0.5 Colon ca. HCC-2998 0.6 0.3 Gastric ca.* (livermet) NCI-N87 0.5 1.2 Bladder 1.8 1.0 Trachea 0.6 1.3 Kidney 1.3 2.5Kidney (fetal) 1.7 4.0 Renal ca. 786-0 3.8 3.7 Renal ca. A498 2.6 3.0Renal ca. RXF 393 2.2 2.3 Renal ca. ACHN 1.1 0.8 Renal ca. UO-31 0.5 1.2Renal ca. TK-10 3.7 3.6 Liver 0.8 0.0 Liver (fetal) 0.2 0.0 Liver ca.(hepatoblast) HepG2 0.7 0.8 Lung 0.2 0.7 Lung (fetal) 0.4 0.6 Lung ca.(small cell) LX-1 1.2 0.1 Lung ca. (small cell) NCI-H69 44.8 40.9 Lungca. (s. cell var.) SHP-77 5.6 5.2 Lung ca. (large cell) NCI-H460 54.374.2 Lung ca. (non-sm. cell) A549 0.5 0.0 Lung ca. (non-s. cell) NCI-H231.5 2.0 Lung ca. (non-s. cell) HOP-62 7.0 5.3 Lung ca. (non-s. cl)NCI-H522 1.1 0.0 Lung ca. (squam.) SW 900 0.3 0.8 Lung ca. (squam.)NCI-H596 8.4 11.1 Mammary gland 2.4 2.0 Breast ca.* (pl. effusion) MCF-71.0 0.7 Breast ca.* (pl. ef) MDA-MB-231 0.0 0.0 Breast ca.* (pl.effusion) T47D 17.3 18.7 Breast ca. BT-549 4.2 4.7 Breast ca. MDA-N 9.39.9 Ovary 12.4 9.9 Ovarian ca. OVCAR-3 0.1 0.0 Ovarian ca. OVCAR-4 0.52.7 Ovarian ca. OVCAR-5 0.9 0.9 Ovarian ca. OVCAR-8 2.1 4.0 Ovarian ca.IGROV-1 0.4 0.3 Ovarian ca. (ascites) SK-OV-3 0.8 0.0 Uterus 1.2 0.7Placenta 1.8 0.1 Prostate 0.5 0.6 Prostate ca.* (bone met) PC-3 3.1 2.2Testis 1.2 1.3 Melanoma Hs688(A).T 0.8 0.9 Melanoma* (met) Hs688(B).T1.2 2.7 Melanoma UACC-62 0.7 0.7 Melanoma M14 4.0 5.5 Melanoma LOX IMVI1.6 0.3 Melanoma* (met) SK-MEL-5 4.2 3.7 Adipose 3.1 1.9

[0478] TABLE 19 Panel 2D Relative Expression (%) Tissue Name2Dtm3026t_ag2120 2Dtm3035t_ag2120 Normal Colon GENPAK 061003 7.3 7.483219 CC Well to Mod Diff (ODO3866) 4.3 7.9 83220 CC NAT (ODO3866) 1.72.9 83221 CC Gr. 2 rectosigmoid (ODO3868) 2.3 1.5 83222 CC NAT (ODO3868)1.7 3.8 83235 CC Mod Diff (ODO3920) 0.2 0.9 83236 CC NAT (ODO3920) 0.12.5 83237 CC Gr. 2 ascend colon (ODO3921) 0.5 0.4 83238 CC NAT (ODO3921)5.8 6.4 83241 CC from Partial Hepatectomy (ODO4309) 6.1 8.7 83242 LiverNAT (ODO4309) 4.0 2.2 87472 Colon mets to lung (OD04451-01) 0.0 0.387473 Lung NAT (OD04451-02) 2.9 3.9 Normal Prostate Clontech A + 6546-13.0 7.8 84140 Prostate Cancer (OD04410) 8.5 9.0 84141 Prostate NAT(OD04410) 23.5 21.5 87073 Prostate Cancer (OD04720-01) 7.3 7.1 87074Prostate NAT (OD04720-02) 1.7 11.3 Normal Lung GENPAK 061010 9.2 7.283239 Lung Met to Muscle (ODO4286) 0.7 0.7 83240 Muscle NAT (ODO4286)11.3 12.5 84136 Lung Malignant Cancer (OD03126) 7.9 4.7 84137 Lung NAT(OD03126) 6.4 7.5 84871 Lung Cancer (OD04404) 3.0 3.8 84872 Lung NAT(OD04404) 2.6 2.8 84875 Lung Cancer (OD04565) 1.8 3.4 84876 Lung NAT(OD04565) 3.6 2.8 85950 Lung Cancer (OD04237-01) 22.5 17.3 85970 LungNAT (OD04237-02) 3.5 4.5 83255 Ocular Mel Met to Liver (ODO4310) 2.1 4.183256 Liver NAT (ODO4310) 1.2 1.2 84139 Melanoma Mets to Lung (OD04321)2.5 1.7 84138 Lung NAT (OD04321) 5.3 3.3 Normal Kidney GENPAK 06100893.3 100.0 83786 Kidney Ca, Nuclear grade 2 (OD04338) 55.9 92.7 83787Kidney NAT OD04338 37.9 36.6 83788 Kidney Ca Nuclear grade 1/2 (OD04339)67.4 76.3 83789 Kidney NAT (OD04339) 25.3 33.2 83790 Kidney Ca, Clearcell type (OD04340) 52.5 43.5 83791 Kidney NAT (OD04340) 0.0 35.6 83792Kidney Ca. Nuclear grade 3 (OD04348) 5.0 7.6 83793 Kidney NAT (OD04348)20.7 26.6 87474 Kidney Cancer (OD04622-01) 9.3 7.3 87475 Kidney NAT(OD04622-03) 7.1 10.2 85973 Kidney Cancer (OD04450-01) 27.0 29.3 85974Kidney NAT (OD04450-03) 34.2 33.7 Kidney Cancer Clontech 8120607 4.1 3.3Kidney NAT Clontech 8120608 9.2 12.8 Kidney Cancer Clontech 8120613 2.23.3 Kidney NAT Clontech 8120614 7.3 14.9 Kidney Cancer Clontech 901032022.4 26.4 Kidney NAT Clontech 9010321 18.3 26.8 Normal Uterus GENPAK061018 9.6 8.6 Uterus Cancer GENPAK 064011 2.7 2.6 Normal ThyroidClontech A + 6570-1 5.1 5.3 Thyroid Cancer GENPAK 064010 39.2 44.1Thyroid Cancer INVITROGEN A302152 30.8 24.5 Thyroid NAT INVITROGENA302153 3.3 3.6 Normal Breast GENPAK 061019 5.0 4.5 84877 Breast Cancer(OD04566) 0.8 1.7 85975 Breast Cancer (OD04590-01) 9.7 7.6 85976 BreastCancer Mets (OD04590-03) 26.1 33.4 87070 Breast Cancer Metastasis(OD04655-05) 3.4 4.1 GENPAK Breast Cancer 064006 3.3 4.4 Breast CancerRes. Gen. 1024 7.2 8.3 Breast Cancer Clontech 9100266 3.1 3.7 Breast NATClontech 9100265 3.3 3.9 Breast Cancer INVITROGEN A209073 8.2 8.9 BreastNAT INVITROGEN A2090734 16.2 11.6 Normal Liver GENPAK 061009 1.4 0.9Liver Cancer GENPAK 064003 1.8 5.1 Liver Cancer Research Genetics RNA1025 1.3 2.0 Liver Cancer Research Genetics RNA 1026 3.4 2.4 PairedLiver Cancer Tissue Research Genetics KNA 6004-T 1.6 0.4 Paired LiverTissue Research Genetics RNA 6004-N 1.3 1.0 Paired Liver Cancer TissueResearch Genetics RNA 6005-T 0.0 6.5 Paired Liver Tissue ResearchGenetics RNA 6005-N 1.6 0.3 Normal Bladder GENPAK 061001 3.4 9.5 BladderCancer Research Genetics RNA 1023 10.7 6.5 Bladder Cancer INVITROGENA302173 1.8 2.1 87071 Bladder Cancer (OD04718-01) 1.7 5.2 87072 BladderNormal Adjacent (OD04718-03) 4.2 6.3 Normal Ovary Res. Gen. 9.5 7.4Ovarian Cancer GENPAK 064008 100.0 95.3 87492 Ovary Cancer (OD04768-07)4.6 7.6 87493 Ovary NAT (OD04768-08) 7.3 5.7 Normal Stomach GENPAK061017 1.7 3.8 Gastric Cancer Clontech 9060358 2.1 0.5 NAT StomachClontech 9060359 1.6 3.1 Gastric Cancer Clontech 9060395 3.3 3.1 NATStomach Clontech 9060394 2.2 3.3 Gastric Cancer Clontech 9060397 11.014.5 NAT Stomach Clontech 9060396 2.8 4.3 Gastric Cancer GENPAK 0640052.2 6.5

[0479] TABLE 20 Panel 4D Relative Relative Expression (%) Expression (%)Tissue Name 4Dtm3027t_ag2120 Tissue Name 4Dtm3027t_ag212093768_Secondary Th1_anti- 0.4 93100_HUVEC 11.2 CD28/anti-CD3(Endothelial)_IL-1b 93769_Secondary Th2_anti- 0.8 93779_HUVEC 10.1CD28/anti-CD3 (Endothelial)_IFN gamma 93770_Secondary Tr1_anti- 3.193102_HUVEC 4.1 CD28/anti-CD3 (Endothelial)_TNF alpha + IFN gamma93573_Secondary Th1_resting 3.4 93101_HUVEC 13.2 day 4-6 in IL-2(Endothelial)_TNF alpha + IL4 93572_Secondary Th2_resting 1.593781_HUVEC 8.1 day 4-6 in IL-2 (Endothelial)_IL-11 93571_SecondaryTr1_resting 1.5 93583_Lung Microvascular 3.2 day 4-6 in IL-2 EndothelialCells_none 93568_primary Th1_anti- 0.3 93584_Lung Microvascular 2.4CD28/anti-CD3 Endothelial Cells_TNFa (4 ng/ml) and IL1b (1 ng/ml)93569_primary Th2_anti- 0.8 92662_Microvascular Dermal 0.0 CD28/anti-CD3endothelium_none 93570_primary Tr1_anti- 0.4 92663_Microsvasular Dermal0.0 CD28/anti-CD3 endothelium_TNFa (4 ng/ml) and IL1b (1 ng/ml)93565_primary Th1_resting dy 3.1 93773_Bronchial 3.1 4-6 in IL-2epithelium_TNFa (4 ng/ml) and IL1b (1 ng/ml)** 93566_primary Th2_restingdy 5.5 93347_Small Airway 5.4 4-6 in IL-2 Epithelium_none 93567_primaryTr1_resting dy 0.6 93348_Small Airway 3.0 4-6 in IL-2 Epithelium_TNFa (4ng/ml) and IL1b (1 ng/ml) 93351_CD45RA CD4 1.3 92668_Coronery Artery35.6 lymphocyte_anti-CD28/anti-CD3 SMC_resting 93352_CD45RO CD4 2.492669_Coronery Artery 39.0 lymphocyte_anti-CD2 8/anti-CD3 SMC_TNFa (4ng/ml) and IL1b (1 ng/ml) 93251_CD8 Lymphocytes_anti- 2.293107_astrocytes_resting 1.1 CD28/anti-CD3 93353_chronic CD8 4.893108_astrocytes_TNFa (4 0.9 Lymphocytes 2ry_resting dy 4-6 ng/ml) andIL1b (1 ng/ml) in IL-2 93574_chronic CD8 2.4 92666_KU-812 0.5Lymphocytes 2ry_activated (Basophil)_resting CD3/CD28 93354_CD4_none 0.992667_KU-812 2.0 (Basophil)_PMA/ionoycin 93252_Secondary 0.793579_CCD1106 0.9 Th1/Th2/Tr1_anti-CD95 CH11 (Keratinocytes)_none93103_LAK cells_resting 7.2 93580_CCD1106 2.6 (Keratinocytes)_TNFa andIFNg** 93788_LAK cells_IL-2 0.4 93791_Liver Cirrhosis 5.5 93787_LAKcells_IL-2 + IL-12 2.8 93792_Lupus Kidney 9.3 93789_LAK cells_IL-2 + IFN7.7 93577_NCI-H292 2.0 gamma 93790_LAK cells_IL-2 + IL-18 4.193358_NCI-H292_IL-4 5.3 93104_LAK 3.2 93360_NCI-H292_IL-9 3.8cells_PMA/ionomycin and IL- 18 93578_NK Cells IL-2_resting 2.393359_NCI-H292_IL-13 1.3 93109_Mixed Lymphocyte 2.7 93357_NCI-H292_IFNgamma 3.4 Reaction_Two Way MLR 93110_Mixed Lymphocyte 4.0 93777_HPAEC_9.0 Reaction_Two Way MLR 93111_Mixed Lymphocyte 5.2 93778_HPAEC_IL-1beta/TNA 15.4 Reaction_Two Way MLR alpha 93112_Mononuclear Cells 6.493254_Normal Human Lung 1.7 (PBMCs)_resting Fibroblast_none93113_Mononuclear Cells 5.2 93253_Normal Human Lung 0.0 (PBMCs)_PWMFibroblast_TNFa (4 ng/ml) and IL-1b (1 ng/ml) 93114_Mononuclear Cells1.8 93257_Normal Human Lung 2.8 (PBMCs)_PHA-L Fibroblast_IL-493249_Ramos (B cell) none 3.9 93256_Normal Human Lung 1.6Fibroblast_IL-9 93250_Ramos (B 1.6 93255_Normal Human Lung 1.0cell)_ionomycin Fibroblast_IL-13 93349_B lymphocytes_PWM 0.093258_Normal Human Lung 1.4 Fibroblast_IFN gamma 93350_Blymphoytes_CD40L 3.2 93106_Dermal Fibroblasts 0.6 and IL-4CCD1070_resting 92665_EOL-1 67.4 93361_Dermal Fibroblasts 2.3(Eosinophil)_dbcAMP CCD1070_TNF alpha 4 ng/ml differentiated 93248_EOL-156.6 93105_Dermal Fibroblasts 5.4 (Eosinophil)_dbcAMP/PMAionomycinCCD1070_IL-1 beta 1 ng/ml 93356_Dendritic Cells_none 6.0 93772_dermalfibroblast_IFN 0.5 gamma 93355_Dendritic Cells_LPS 15.5 93771_dermalfibroblast IL-4 3.0 100 ng/ml 93775_Dendritic Cells_anti- 13.5 93259_IBDColitis 1** 1.3 CD40 93774_Monocytes_resting 46.0 93260_IBD Colitis 25.8 93776_Monocytes_LPS 50 4.9 93261_IBD Crohns 4.2 ng/ml93581_Macrophages_resting 47.3 735010_Colon_normal 5.893582_Macrophages_LPS 100 24.8 735019_Lung_none 7.0 ng/ml 93098_HUVEC10.2 64028-1_Thymus_none 100.0 (Endothelial)_none 93099_HUVEC 23.864030-1_Kidney_none 18.2 (Endothelial)_starved

[0480] TABLE 21 Panel CNSD.01 Relative Relative Expression (%)Expression (%) Tissue Name CNS1x4tm6184t_ag2120_a2 Tissue NameCNS1x4tm6184t_ag2120_a2 102633_BA4 Control 46.5 102605_BA17 PSP 20.1102641_BA4 Control2 42.9 102612_BA17 PSP2 10.5 102625_BA4 Alzheimer's25.2 102637_Sub Nigra Control 10.6 102649_BA4 Parkinson's 38.5 102645_SubNigra Control2 29.1 102656_BA4 Parkinson's2 100.0 102629_Sub Nigra 5.8Alzheimer's2 102664_BA4 Huntington's 53.8 102660_Sub Nigra Parkinson's220.6 102671_BA4 Huntington's2 4.3 102667_Sub Nigra 21.5 Huntington's102603_BA4 PSP 4.5 102674_Sub Nigra 14.7 Huntington's2 102610_BA4 PSP214.1 102614_Sub Nigra PSP2 3.6 102588_BA4 Depression 11.8 102592_SubNigra Depression 3.2 102596_BA4 Depression2 3.5 102599_Sub NigraDepression2 2.4 102634_BA7 Control 45.6 102636_Glob Palladus Control 1.8102642_BA7 Control2 37.9 102644_Glob Palladus Control2 7.8 102626_BA7Alzheimer's2 8.5 102620_Glob Palladus 6.4 Alzheimer's 102650_BA7parkinson's 11.7 102628_Glob Palladus 2.5 Alzheimer's2 102657_BA7Parkinson's2 54.6 102652_Glob Palladus 34.4 Parkinson's 102665_BA7Huntington's 41.1 102659_Glob Palladus 3.1 Parkinson's2 102672_BA7Huntington's2 34.3 102606_Glob Palladus PSP 5.2 102604_BA7 PSP 36.2102613_Glob Palladus PSP2 0.0 102611_BA7 PSP2 21.2 102591_Glob Palladus3.7 Depression 102589_BA7 Depression 4.5 102638_Temp Pole Control 11.0102632_BA9 Control 18.1 102646_Temp Pole Control2 40.1 102640_BA9Control2 76.7 102622_Temp Pole Alzheimer's 2.7 102617_BA9 Alzheimer's8.0 102630_Temp Pole 3.4 Alzheimer's2 102624_BA9 Alzheimer's2 4.6102653_Temp Pole Parkinson's 13.9 102648_BA9 Parkinson's 28.7102661_Temp Pole 20.8 Parkinson's2 102655_BA9 Parkinson's2 55.5102668_Temp Pole 27.6 Huntington's 102663_BA9 Huntington's 34.2102601_Temp Pole PSP 2.5 102670_BA9 Huntington's2 4.7 102615_Temp PolePSP2 3.7 102602_BA9 PSP 11.6 102600_Temp Pole 1.8 Depression2 102609_BA9PSP2 3.8 102639_Cing Gyr Control 70.7 102587_BA9 Depression 5.0102647_Cing Gyr Control2 23.9 102595_BA9 Depression2 3.2 102623_Cing GyrAlzheimer's 13.8 102635_BA17 Control 37.0 102631_Cing Gyr Alzheimer's27.8 102643_BA17 Control2 62.0 102654_Cing Gyr Parkinson's 13.2102627_BA17 Alzheimer's2 2.9 102662_Cing Gyr Parkinson's2 23.0102651_BA17 Parkinson's 13.4 102669_Cing Gyr Huntington's 40.3102658_BA17 Parkinson's2 61.3 102676_Cing Gyr 12.9 Huntington's2102666_BA17 Huntington's 28.0 102608_Cing Gyr PSP 7.6 102673_BA17Huntington's2 8.4 102616_Cing Gyr PSP2 5.6 102590_BA17 Depression 2.3102594_Cing Gyr Depression 4.1 102597_BA17 Depression2 10.1 102601_CingGyr Depression2 4.6

[0481] Panel 1.3D Summary: Ag2120 Two replicate experiments using thesame probe and primer set show very comparable results. Expression ofthe MOL2 gene is highest in the cerebral cortex (CT value=29). Moderateexpression is detected in all other regions of the brain except thalamusand substantia nigra; this observation suggests that the MOL2 gene maybe associated with normal brain homeostasis. Thus, this protein shows abrain-preferential expression; see write-up on Panel CNS.01 fordiscussion of utility. In addition, expression of the MOL2 gene appearsto be down-regulated in CNS cancer cell lines. Overexpression of theMOL2 gene is also detected in several lung cancer cell lines relative tonormal control. Therefore, this gene might be a good target for thedetection or treatment of CNS and lung cancers.

[0482] Panel 2D Summary: Ag2120 Two replicate experiments using the sameprobe and primer set show very comparable results. Expression of theMOL2 gene in panel 2D reveals an association of expression in thyroid,breast and kidney cancers when compared to their respective normaladjacent tissues. Thus, therapeutic modulation of this gene withinhibitory monoclonal antibodies and/or small moleculte therapeutics mayshow utility in treatment of these diseases. In addition, the MOL2 genemight be useful as a marker for thyroid, breast and kidney cancers.

[0483] Panel 4D Summary: Ag 2120 The MOL2 gene is expressed at highestlevels in the thymus (CT value=31), In addition, the transcript is alsoexpressed in eosinophils, monocytes, macrophages and coronary artery.Interestingly, it is down regulated in LPS-treated monocytes and to alesser degree in LPS treated macrophages. Therefore, proteintherapeutics (agonists or antagonists) designed against the proteinencoded for by this transcript could reduce inflammatory processobserved in asthma, emphysema, osteoarthritis and sepsis.

[0484] Panel CNSD.01 Summary: Ag2120 The insulin and insulin-like growthfactors belong to a family of polypeptides essential for properregulation of physiologic processes such as energy metabolism, cellproliferation, development, and differentiation. The insulin-like growthfactors bind to IGF with high affinity and compete with the IGF receptorfor IGF binding. Transgenic mice overexpressing insulin-like growthfactor binding proteins (IGFBPs) tend to show brain developmentalabnormalities, suggesting a role for these proteins in neurodevelopment.Furthermore, treatment with glycosaminoglycans (which increases musclere-innervation after motor neuron death) upregulates serum levels ofboth IGF and IGFBP. Thus, the novel IGFBP encoded by the MOL2 gene maybe useful in the treatment of diseases such as ALS, multiple sclerosis,and peripheral nerve injury on the basis of its homology to otherestablished IGFBPs. The expression profile of this gene suggests that itis expressed preferentially in the brain, with highest levels in thecerebral cortex and hippocampus, two regions that are known todegenerate in Alzheimer's disease. Examination of the expression profileon Panel CNS.01 shows that most regions of both control and diseasedbrains express this protein; however the levels are decreased in themotor cortex in progressive supranuclear palsy and depression. Thus,this protein may additionally be of use in the treatment of Alzheimer'sdisease, progressive supranuclear palsy, and depression.

[0485] C. MOL3a

[0486] Expression of gene MOL3a was assessed using the primer-probe setAg1493, described in Table 22. Results of the RTQ-PCR runs are shown inTables 23, 24, 25, and 26. TABLE 22 Probe Name Ag1493 Start PrimersSequences TM Length Position SEQ ID NO: Forward5′-GTGAAATCTGGCGTGGAGTATA-3′ 59.1 22 1224 74 ProbeFAM-5′-CCTTGATGGGCACAGCCATCTTG- 70 23 1274 75 3′-TAMRA Reverse5′-GTACTGGTTCCCAGGTACATGA-3′ 58.8 22 1318 76

[0487] TABLE 23 Panel 1.2 Relative Relative Expression (%) Expression(%) Tissue Name 1.2tm2058f_ag1493 Tissue Name 1.2tm2058f_ag1493Endothelial cells 0.2 Renal ca. 786-0 0.0 Endothelial cells (treated)2.4 Renal ca. A498 0.5 Pancreas 0.1 Renal ca. RXF 393 0.9 Pancreatic ca.CAPAN 2 0.1 Renal ca. ACHN 0.2 Adrenal Gland (new lot*) 2.6 Renal ca.UO-31 1.3 Thyroid 1.0 Renal ca. TK-10 0.8 Salivary gland 21.8 Liver 1.4Pituitary gland 0.4 Liver (fetal) 2.3 Brain (fetal) 3.3 Liver ca.(hepatoblast) HepG2 0.7 Brain (whole) 2.1 Lung 0.8 Brain (amygdala) 8.0Lung (fetal) 1.0 Brain (cerebellum) 0.3 Lung ca. (small cell) LX-1 0.4Brain (hippocampus) 15.0 Lung ca. (small cell) NCI-H69 1.9 Brain(thalamus) 3.5 Lung ca. (s. cell var.) SHP-77 0.0 Cerebral Cortex 30.1Lung ca. (large cell) NCI-H460 0.7 Spinal cord 0.2 Lung ca. (non-sm.cell) A549 1.0 CNS ca. (glio/astro) U87-MG 0.2 Lung ca. (non-s. cell)NCI-H23 0.2 CNS ca. (glio/astro) U-118-MG 0.3 Lung ca (non-s. cell)HOP-62 1.8 CNS ca. (astro) SW1783 0.0 Lung ca. (non-s. cl) NCI-H522 11.9CNS ca.* (neuro; met) SK-N-AS 0.5 Lung ca. (squam.) SW 900 0.8 CNS ca.(astro) SF-539 0.4 Lung ca. (squam.) NCI-H596 1.0 CNS ca. (astro) SNB-750.1 Mammary gland 2.5 CNS ca. (glio) SNB-19 0.4 Breast ca.* (pl.effusion) MCF-7 3.7 CNS ca. (glio) U251 0.2 Breast ca.* (pl. ef) MDA-MB-0.0 231 CNS ca. (glio) SF-295 1.3 Breast ca.* (pl. effusion) T47D 17.6Heart 5.1 Breast ca. BT-549 0.2 Skeletal Muscle (new lot*) 8.0 Breastca. MDA-N 0.4 Bone marrow 15.6 Ovary 2.7 Thymus 1.2 Ovarian ca. OVCAR-38.3 Spleen 10.4 Ovarian ca. OVCAR-4 16.6 Lymph node 0.7 Ovarian ca.OVCAR-5 5.1 Colorectal 0.9 Ovarian ca. OVCAR-8 0.8 Stomach 2.9 Ovarianca. IGROV-1 70.7 Small intestine 4.7 Ovarian ca.* (ascites) SK-OV-3 0.7Colon ca. SW480 0.2 Uterus 0.6 Colon ca.* (SW480 met) SW620 0.0 Placenta0.6 Colon ca. HT29 2.3 Prostate 27.9 Colon ca. HCT-116 0.0 Prostate ca.*(bone met) PC-3 0.3 Colon ca. CaCo-2 0.0 Testis 0.6 83219 CC Well to ModDiff 1.4 Melanoma Hs688(A).T 0.2 (ODO3866) Colon ca. HCC-2998 2.8Melanoma* (met) Hs688(B).T 0.4 Gastric ca.* (liver met) NCI- 1.6Melanoma UACC-62 0.5 N87 Bladder 6.9 Melanoma M14 0.1 Trachea 0.5Melanoma LOX IMVI 0.1 Kidney 73.7 Melanoma* (met) SK-MEL-5 0.0 Kidney(fetal) 4.7 Adipose 100.0

[0488] TABLE 24 Panel 1.3D Relative Relative Expression (%) Expression(%) Tissue Name 1.3dx4tm5350f_ag1493_b1 Tissue Name1.3dx4tm5350f_ag1493_b1 Liver adenocarcinoma 1.2 Kidney (fetal) 18.7Pancreas 0.0 Renal ca. 786-0 0.0 Pancreatic ca. CAPAN 2 1.9 Renal ca.A498 0.0 Adrenal gland 1.7 Renal ca. RXF 393 2.9 Thyroid 38.0 Renal ca.ACHN 1.0 Salivary gland 30.8 Renal ca. UO-31 0.8 Pituitar gland 4.5Renal ca. IK-b 0.8 Brain (fetal) 48.3 Liver 0.4 Brain (whole) 60.7 Liver(fetal) 11.2 Brain (amygdala) 100.0 Liver ca. (hepatoblast) HepG2 0.6Brain (cerebellum) 9.2 Lung 29.6 Brain (hippocampus) 68.2 Lung (fetal)15.6 Brain (substantia nigra) 11.4 Lung ca. (small cell) LX-1 0.2 Brain(thalamus) 20.8 Lung ca. (small cell) NCI-H69 0.0 Cerebral Cortex 41.1Lung ca. (s. cell var.) SHP-77 0.0 Spinal cord 10.0 Lung ca. (largecell) NCI-H460 0.5 CNS ca. (glio/astro) U87-MG 0.0 Lung ca. (non-sm.cell) A549 0.4 CNS ca. (glio/astro) U-118-MG 1.3 Lung ca. (non-s. cell)NCI-H23 0.0 CNS ca. (astro) SW1783 0.7 Lung ca (non-s. cell) HOP-62 2.6CNS ca.* (neuro; met) SK-N-AS 1.9 Lung ca. (non-s. cl) NCI-H522 3.0 CNSca. (astro) SF-539 0.5 Lung ca. (squam.) SW 900 0.2 CNS ca. (astro)SNB-75 0.4 Lung ca. (squam.) NCI-H596 0.0 CNS ca. (glio) SNB-19 0.4Mammary gland 22.3 CNS ca. (glio) U251 1.2 Breast ca.* (pl. effusion)MCF-7 14.1 CNS ca. (glio) SF-295 0.6 Breast ca.* (pl. ef) MDA-MB- 0.0231 Heart (fetal) 1.3 Breast ca.* (pl. effusion) T47D 53.3 Heart 1.4Breast ca. BT-549 0.5 Fetal Skeletal 4.2 Breast ca. MDA-N 0.0 Skeletalmuscle 8.8 Ovary 2.1 Bone marrow 78.4 Ovarian ca. OVCAR-3 8.7 Thymus 3.9Ovarian ca. OVCAR-4 25.1 Spleen 53.3 Ovarian ca. OVCAR-5 3.8 Lymph node37.3 Ovarian ca. OVCAR-8 2.6 Colorectal 6.6 Ovarian ca. IGROV-1 29.2Stomach 23.1 Ovarian ca.* (ascites) SK-OV-3 0.5 Small intestine 12.5Uterus 8.9 Colon ca. SW480 0.0 Placenta 10.9 Colon ca.* (SW480 met)SW620 0.0 Prostate 50.9 Colon ca. HT29 2.9 Prostate ca.* (bone met) PC-30.0 Colon ca. HCT-116 0.0 Testis 18.7 Colon ca. CaCo-2 0.8 MelanomaHs688(A).T 0.5 83219 CC Well to Mod Diff 8.2 Melanoma* (met) Hs688(B).T0.0 (ODO3866) Colon ca. HCC-2998 0.8 Melanoma UACC-62 0.0 Gastric ca.*(liver met) NCI- 2.8 Melanoma M14 0.5 N87 Bladder 5.3 Melanoma LOX IMVI0.0 Trachea 35.6 Melanoma* (met) SK-MEL-5 0.0 Kidney 15.0 Adipose 60.2

[0489] TABLE 25 Panel 2D Relative Relative Expression (%) Expression (%)Tissue Name 2Dtm2527f_ag1493 Tissue Name 2Dtm2527f_ag1493 Normal ColonGENPAK 41.2 Kidney NAT Clontech 8120608 28.3 061003 83219 CC Well to ModDiff 8.0 Kidney Cancer Clontech 10.7 (ODO3866) 8120613 83220 CC NAT(ODO3866) 9.3 Kidney NAT Clontech 8120614 46.0 83221 CC Gr. 2rectosigmoid 5.1 Kidney Cancer Clontech 48.6 (ODO3868) 9010320 83222 CCNAT (ODO3868) 2.0 Kidney NAT Clontech 9010321 36.6 83235 CC Mod Diff 6.3Normal Uterus GENPAK 8.4 (ODO3920) 061018 83236 CC NAT (ODO3920) 4.4Uterus Cancer GENPAK 17.4 064011 83237 CC Gr. 2 ascend colon 12.5 NormalThyroid Clontech A + 100.0 (ODO3921) 6570-1 83238 CC NAT (ODO3921) 6.1Thyroid Cancer GENPAK 39.8 064010 83241 CC from Partial 17.0 ThyroidCancer INVITROGEN 28.3 Hepatectomy (ODO4309) A302152 83242 Liver NAT(ODO4309) 7.6 Thyroid NAT INVITROGEN 44.4 A302153 87472 Colon mets tolung 16.6 Normal Breast GENPAK 36.3 (OD04451-01) 061019 87473 Lung NAT(OD04451- 25.5 84877 Breast Cancer 24.7 02) (OD04566) Normal ProstateClontech A + 82.4 85975 Breast Cancer 29.7 6546-1 (OD04590-01) 84140Prostate Cancer 36.3 85976 Breast Cancer Mets 17.8 (OD04410)(OD04590-03) 84141 Prostate NAT 47.0 87070 Breast Cancer Metastasis 79.6(OD04410) (OD04655-05) 87073 Prostate Cancer 36.1 GENPAK Breast Cancer25.9 (OD04720-01) 064006 87074 Prostate NAT 51.4 Breast Cancer Res. Gen.1024 55.5 (OD04720-02) Normal Lung GENPAK 061010 41.8 Breast CancerClontech 24.0 9100266 83239 Lung Met to Muscle 14.4 Breast NAT Clontech9100265 13.7 (ODO4286) 83240 Muscle NAT 4.5 Breast Cancer INVITROGEN29.1 (ODO4286) A209073 84136 Lung Malignant Cancer 36.1 Breast NATINVITROGEN 29.9 (OD03126) A2090734 84137 Lung NAT (OD03126) 71.2 NormalLiver GENPAK 1.0 061009 84871 Lung Cancer (OD04404) 68.3 Liver CancerGENPAK 064003 1.6 84872 Lung NAT (OD04404) 33.7 Liver Cancer ResearchGenetics 7.4 RNA 1025 84875 Lung Cancer (OD04565) 25.5 Liver CancerResearch Genetics 4.3 RNA 1026 84876 Lung NAT (OD04565) 18.4 PairedLiver Cancer Tissue 8.5 Research Genetics RNA 6004-T 85950 Lung Cancer(OD04237- 45.1 Paired Liver Tissue Research 10.1 01) Genetics RNA 6004-N85970 Lung NAT (OD04237- Paired Liver Cancer Tissue 7.5 02) ResearchGenetics RNA 6005-T 83255 Ocular Mel Met to Liver 8.7 Paired LiverTissue Research 2.8 (ODO4310) Genetics RNA 6005-N 83256 Liver NAT(ODO4310) 4.7 Normal Bladder GENPAK 11.7 061001 84139 Melanoma Mets toLung 4.0 Bladder Cancer Research 6.4 (OD04321) Genetics RNA 1023 84138Lung NAT (OD04321) 50.3 Bladder Cancer INVITROGEN 50.3 A302173 NormalKidney GENPAK 53.2 87071 Bladder Cancer 35.4 061008 (OD04718-01) 83786Kidney Ca, Nuclear 13.6 87072 Bladder Normal 13.6 grade 2 (OD04338)Adjacent (OD04718-03) 83787 Kidney NAT (OD04338) 54.0 Normal Ovary Res.Gen. 6.4 83788 Kidney Ca Nuclear grade 23.0 Ovarian Cancer GENPAK 22.11/2 (OD04339) 064008 83789 Kidney NAT (OD04339) 26.6 87492 Ovary Cancer29.3 (OD04768-07) 83790 Kidney Ca, Clear cell 31.0 87493 Ovary NAT(OD04768- 20.7 type (OD04340) 08) 83791 Kidney NAT (OD04340) 49.7 NormalStomach GENPAK 21.9 061017 83792 Kidney Ca, Nuclear 7.8 Gastric CancerClontech 12.6 grade 3 (OD04348) 9060358 83793 Kidney NAT (OD04348) 35.8NAT Stomach Clontech 33.7 9060359 87474 Kidney Cancer 17.8 GastricCancer Clontech 15.6 (OD04622-01) 9060395 87475 Kidney NAT (OD04622-15.4 NAT Stomach Clontech 51.8 03) 9060394 85973 Kidney Cancer 1.7Gastric Cancer Clontech 16.8 (OD04450-01) 9060397 85974 Kidney NAT(OD04450- 43.2 NAT Stomach Clontech 12.4 03) 9060396 Kidney CancerClontech 4.3 Gastric Cancer GENPAK 12.9 8120607 064005

[0490] TABLE 26 Panel 4.1D Relative Relative Expression (%) Expression(%) Tissue Name 4.1dx4tm6520f_ag1493_a1 Tissue Name4.1dx4tm6520f_1493_a1 93768_Secondary Th1_anti- 3.8 93100_HUVEC 0.0CD28/anti-CD3 (Endothelial)_IL-1b 93769_Secondary Th2_anti- 27.093779_HUVEC 0.6 CD28/anti-CD3 (Endothelial)_IFN gamma 93770_SecondaryTr1_anti- 11.9 93102_HUVEC 1.0 CD28/anti-CD3 (Endothelial)_TNF alpha +IFN gamma 93573_Secondary Th1_resting 1.1 93101_HUVEC 0.9 day 4-6 inIL-2 (Endothelial)_TNF alpha + IL4 93572_Secondary Th2_resting 3.293781_HUVEC 0.6 day 4-6 in IL-2 (Endothelial)_IL-11 93571_SecondaryTr1_resting 1.6 93583_Lung Microvascular 1.6 day 4-6 in IL-2 EndothelialCells_none 93568_primary Th1_anti- 6.7 93584_Lung Microvascular 0.6CD28/anti-CD3 Endothelial Cells_TNFa (4 ng/ml) and IL1b (1 ng/ml)93569_primary Th2_anti- 8.4 92662_Microvascular Dermal 0.2 CD28/anti-CD3endothelium_none 93570_primary Tr1_anti- 1.9 92663_Microsvasular Dermal0.3 CD28/anti-CD3 endothelium_TNFa (4 ng/ml) and IL1b (1 ng/ml)93565_primary Th1_resting dy 0.4 93773_Bronchial 2.1 4-6 in IL-2epithelium_TNFa (4 ng/ml) and IL1b (1 ng/ml)** 93566_primary Th2_restingdy 0.7 93347_Small Airway 1.0 4-6 in IL-2 Epithelium_none 93567_primaryTr1_resting dy 0.2 93348_Small Airway 4.2 4-6 in IL-2 Epithelium_TNFa (4ng/ml) and IL1b (1 ng/ml) 93351_CD45RA CD4 3.8 92668_Coronery Artery 0.1lymphocyte_anti-CD28/anti- SMC_resting CD3 93352_CD4SRO CD4 7.192669_Coronery Artery 0.4 lymphocyte_anti-CD28/anti- SMC_TNFa (4 ng/ml)and IL1b CD3 (1 ng/ml) 93251_CD8 Lymphocytes_anti- 6.193107_astrocytes_resting 0.1 CD28/anti-CD3 93353_chronic CD8 25.693108_astrocytes_TNFa (4 0.0 Lymphocytes 2ry_resting dy 4-6 ng/ml) andIL1b (1 ng/ml) in IL-2 93574_chronic CD8 9.9 92666_KU-812 0.3Lymphocytes 2ry_activated (Basophil)_resting CD3/CD28 93354_CD4_none 0.592667_KU-812 0.5 (Basophil)_PMA/ionoycin 93252_Secondary 1.293579_CCD1106 4.2 Th1/Th2/Tr1_anti-CD95 CH11 (Keratinocytes)_none93103_LAK cells_resting 25.6 93580_CCD1106 4.0 (Keratinocytes)_TNFa andIFNg** 93788_LAK cells_IL-2 3.2 93791_Liver Cirrhosis 1.7 93787_LAKcells_IL-2 + IL-12 6.4 93577_NCI-H292 3.3 93789_LAK cells_IL-2 + IFN 5.393358_NCI-H292_IL-4 5.5 gamma 93790_LAK cells_IL-2 + IL-18 4.693360_NCI-H292 IL-9 4.6 93104_LAK 11.6 93359_NCI-H292_IL-13 6.3cells_PMA/ionomycin and IL-18 93578_NK Cells IL-2_resting 3.093357_NCI-H292_IFN gamma 3.4 93109_Mixed Lymphocyte 17.2 93777_HPAEC_0.2 Reaction_Two Way MLR 93110_Mixed Lymphocyte 13.5 93778_HPAEC_IL-1beta/TNA 0.5 Reaction_Two Way MLR alpha 93111_Mixed Lymphocyte 5.493254_Normal Human Lung 0.5 Reaction_Two Way MLR Fibroblast_none93112_Mononuclear Cells 9.1 93253_Normal Human Lung 0.3 (PBMCs)_restingFibroblast_TNFa (4 ng/ml) and IL-1b (1 ng/ml) 93113_Mononuclear Cells11.5 93257_Normal Human Lung 0.2 (PBMCs)_PWM Fibroblast_IL-493114_Mononuclear Cells 20.5 93256_Normal Human Lung 0.3 (PBMCs)_3HA-LFibroblast_IL-9 93249_Ramos (B cell)_none 70.5 93255_Normal Human Lung0.6 Fibroblast_IL-13 93250_Ramos (B 100.0 93258_Normal Human Lung 0.5cell)_ionomycin Fibroblast_IFN gamma 93349_B lymphocytes_PWM 12.493106_Dermal Fibroblasts 0.5 CCD1070_resting 93350_B lymphoytes_CD40L64.9 93361_Dermal Fibroblasts 4.1 and IL-4 CCD1070_TNF alpha 4 ng/ml92665_EOL-1 10.0 93105_Dermal Fibroblasts 0.1 (Eosinophil)_dbcAMPCCD1070_IL-1 beta 1 ng/ml differentiated 93248_EOL-1 6.9 93772_dermalfibroblast IFN 1.0 (Eosinophil)_dbcAMP/PMAionomycin gamma93356_Dendritic Cells none 10.1 93771_dermal fibroblast IL-4 2.293355_Dendritic Cells_LPS 21.1 93892_Dermal fibroblasts_none 1.0 100ng/ml 93775_Dendritic Cells_anti- 9.9 99202_Neutrophils_TNFa + LPS 9.2CD40 93774_Monocytes_resting 38.2 99203_Neutrophils_none 38.193776_Monocytes_LPS 50 51.1 735010_Colon_normal 1.2 ng/ml93581_Macrophages_resting 18.4 735019_Lung_none 5.593582_Macrophages_LPS 100 19.7 64028-1_Thymus_none 8.2 ng/ml 93098_HUVEC0.0 64030-1_Kidney_none 9.8 (Endothelial)_none 93099_HUVEC 0.3(Endothelial)_starved

[0491] TABLE 27 Panel CNSD.01 Relative Relative Expression (%)Expression (%) Tissue Name cns1x4tm6179f_ag1493_b1 Tissue Namecns1x4tm6179f_ag1493_b1 102633_BA4 Control 14.8 102605_BA17 PSP 15.9102641_BA4 Control2 51.1 102612_BA17 PSP2 8.3 102625_BA4 Alzheimer's23.6 102637_Sub Nigra Control 28.5 102649_BA4 parkinson's 36.3 102645_SubNigra Control2 47.1 102656_BA4 Parkinson's2 54.3 102629_Sub Nigra 3.3Alzheimer's2 102664_BA4 Huntington's 17.2 102660_Sub Nigra Parkinson's261.6 102671_BA4 Huntington's2 4.3 102667_Sub Nigra 37.6 Huntington's102603_BA4 PSP 0.0 102674_Sub Nigra 8.2 Huntington's2 102610_BA4 PSP214.0 102614_Sub Nigra PSP2 4.6 102588_BA4 Depression 14.9 102592_SubNigra Depression 6.8 102596_BA4 Depression 22.6 102599_Sub NigraDepression2 6.6 102634_BA7 Control 16.5 102636_Glob Palladus Control10.2 102642_BA7 Control2 13.7 102644_Glob Palladus Control2 9.0102626_BA7 Alzheimer's2 3.9 102620_Glob Palladus 4.4 Alzheimer's102650_BA7 Parkinson's 18.2 102628_Glob Palladus 2.6 Alzheimer's2102657_BA7 Parkinson's2 45.6 102652_Glob Palladus 80.4 Parkinson's102665_BA7 Huntington's 35.9 102659_Glob Palladus 5.2 Parkinson's2102672_BA7 Huntington's2 18.7 102606_Glob Palladus PSP 6.4 102604_BA7PSP 54.8 102613_Glob Palladus PSP2 2.7 102611_BA7 PSP2 17.8 102591_GlobPalladus 4.0 Depression 102589_BA7 Depression 11.2 102638_Temp PoleControl 13.8 102632_BA9 Control 16.1 102646_Temp Pole Control2 100.0102640_BA9 Control2 96.5 102622_Temp Pole Alzheimer's 0.8 102617_BA9Alzheimer's 0.0 102630_Temp Pole 3.0 Alzheimer's2 102624_BA9Alzheimer's2 7.0 102653_Temp Pole Parkinson's 51.3 102648_BA9Parkinson's 29.5 102661_Temp Pole 34.2 Parkinson's2 102655_BA9Parkinson's2 47.8 102668_Temp Pole 50.4 Huntington's 102663_BA9Huntington's 27.6 102607_Temp Pole PSP 1.2 102670_BA9 Huntington's2 14.9102615_Temp Pole PSP2 1.7 102602_BA9 PSP 9.0 102600_Temp Pole 8.9Depression2 102609_BA9 PSP2 3.1 102639_Cing Gyr Control 50.1 102587_BA9Depression 3.2 102647_Cing Gyr Control2 55.7 102595_BA9 Depression 25.3102623_Cing Gyr Alzheimer's 18.9 102635_BA17 Control 17.9 102631_CingGyr Alzheimer's2 0.9 102643_BA17 Control2 37.2 102654_Cing GyrParkinson's 35.5 102627_BA17 Alzheimer's2 5.7 102662_Cing GyrParkinson's2 84.5 102651_BA17 Parkinson's 45.7 102669_Cing GyrHuntington's 67.5 102658_BA17 Parkinson's2 18.1 102678_Cing Gyr 23.3Huntington's2 102666_BA17 Huntington's 15.1 10260_Cing Gyr PSP 14.0102673_BA17 Huntington's2 13.0 102616_Cing Gyr PSP2 7.9 102590_BA17Depression 9.4 102594_Cing Gyr Depression 3.0 102597_BA17 Depression231.9 102601_Cing Gyr Depression2 11.8

[0492] Panel 1.2 Summary: Ag1493 The high expression of the MOL3a geneseen in adipose (CT value=25) is most likely skewed due to genomic DNAcontamination in this sample. Otherwise, the gene is expressed mainly innormal tissues, including brain (particularly cerebral cortex), kidney,and prostate. Expression of the MOL3a gene in skeletal muscle and livermay suggest function in metabolic diseases, including obesity anddiabetes. Furthermore, MOL3a expression is down regulated in a number oftumor cell lines relative to the normal controls suggesting a potentialutility of this gene in the treatment of cancer.

[0493] Panel 1.3D Summary: Ag1493 In this panel, highest expression ofthe MOL3a gene is detected in the amygdala of the brain (CT value=29.6).This may suggest that the MOL3a gene plays a role in normal brainfunction, including fear and anxiety response. In addition, highexpression is also observed in adipose and bone marrow suggestingpotential roles in metabolic and immune function. Overall, expression ofthe MOL3a gene in panel 1.3D reveals that it is associated mostly withnormal tissues. In a couple of instances, the expression of this gene isseen in clusters of cell lines, specifically in breast and ovariancancer cell lines. Thus, therapeutic modulation of expression of thisgene may be of utility in the treatment breast and ovarian cancers.Alternatively, replacement of the MOL3a protein that is missing fromsome cancer cells using recombinant protein might provide a usefultreatment for these types of cancers.

[0494] Panel 2D Summary: Ag1493 Expression of the MOL3a gene is highestin thyroid and appears to be widespread across many samples on Panel 2D.However, overall there appears to be generally higher expression innormal tissues when compared to cancerous counterparts. Thus,therapeutic modulation of this gene or gene product might show utilityfor a range of oncology indications. Semaphorins and their receptors areknown signals for axon guidance; they are also suspected to regulatedevelopmental processes involving cell migration and morphogenesis, andhave been implicated in immune function and tumor progression.

[0495] Panel 4.1D Summary: Ag1493 The MOL3a transcript is highlyexpressed in a B cell line as well as in B cells stimulated with CD40Land IL4. Expression of this transcript is also found to a lesser degreein monocytes and macrophages independently of their activation status.Of interest, CD100, which is an activation molecule on T cells, is amember of the semaphorin protein family. The semaphorin B-like proteinencoded by the MOL3a transcript could therefore also serve as a B cellactivation marker. The semaphorin family has additionally been reportedto play a role in chemotaxis. Thus, protein therapeutics or monoclonalantibodies raised against the MOL3a protein, could inhibit spontaneousand chemokine induced migration of B cells and monocytes and potentiallyregulate B cell differentiation and B cell isotype switching. Regulationof this molecule by protein therapeutics or monoclonal antibodies couldalso function to regulate immunity and be important for the treatment ofautoimmune diseases, allergic diseases, and immune rejection intransplantation. In support of this hypothesis, recent studies indicatethat semaphorins bind with high affinity to at least two differentreceptor families and are biologically active on immune cells as well asneuronal cells (Curr Opin Immunol 1999 August;11(4):387-91).

[0496] Panel CNSD.01 Summary: Ag1493 Semaphorins can act as axonguidance proteins, specifically through their ability to act aschemorepellents that inhibit CNS regenerative capacity. Although thereis considerable variance between individuals in MOL3a gene expressionlevels in this panel, levels of this protein are reduced to less than ⅓of that seen in controls in the temporal cortex of Alzheimer's patients(which shows marked synaptogenic loss in mid to late phases of thedisease) as well as in diseases not associated with neurodegeneration ofthe temporal cortex. Therefore, manipulation of levels of this proteinmay be of use in inducing a compensatory synaptogenic response toneuronal death in Alzheimer's disease

[0497] D. MOL4

[0498] Expression of gene MOL4 was assessed using the primer-probe setAg1216, described in Table 28. Results of the RTQ-PCR runs are shown inTables 29, 30, 31, and 32. TABLE 28 Probe Name: Ag1216 Start PrimersSequences TM Length Position SEQ ID NO: Forward5′-CCCGAAGAATGAAAAGTACACA-3′ 59.1 22 5263 77 Probe FAM-5′- 69.7 26 528578 CCCATGGAATTCAAGACCCTGAACAA-3′- TAMRA Reverse5′-AATGGGTAGAAGTTGGCTCTGT-3′ 59.2 22 5331 79

[0499] TABLE 29 Panel 1.2 Relative Relative Expression (%) Expression(%) Tissue Name 1.2tm1404f_ag1216 Tissue Name 1.2tm1404f_ag1216Endothelial cells 0.0 Renal ca. 786-0 100.0 Endothelial cells (treated)76.8 Renal ca. A498 3.0 Pancreas 11.3 Renal ca. RXF 393 45.4 Pancreaticca. CAPAN 2 0.0 Renal ca. ACHN 0.2 Adrenal Gland (new lot*) 12.2 Renalca. UO-31 0.0 Thyroid 11.6 Renal ca. TK-10 0.0 Salivary gland 2.7 Liver7.5 Pituitary gland 12.6 Liver (fetal) 7.7 Brain (fetal) 77.9 Liver ca.(hepatoblast) HepG2 0.0 Brain (whole) 73.2 Lung 6.1 Brain (amygdala)33.7 Lung (fetal) 13.1 Brain (cerebellum) 6.8 Lung ca. (small cell) LX-10.0 Brain (hippocampus) 75.3 Lung ca. (small cell) NCI-H69 0.0 Brain(thalamus) 9.9 Lung ca. (s. cell var.) SHP-77 0.0 Cerebral Cortex 87.7Lung ca. (large cell) NCI-H460 0.0 Spinal cord 8.3 Lung ca. (non-sm.cell) A549 0.0 CNS ca. (glio/astro) U87-MG 0.0 Lung ca. (non-s. cell)NCI-H23 0.0 CNS ca. (glio/astro) U-118-MG 1.5 Lung ca (non-s. cell)HOP-62 0.0 CNS ca. (astro) SW1783 0.0 Lung ca. (non-s. cl) NCI-H522 0.0CNS ca.* (neuro; met) SK-N-AS 11.1 Lung ca. (squam.) SW 900 0.0 CNS ca.(astro) SF-539 0.0 Lung ca. (squam.) NCI-H596 0.0 CNS ca. (astro) SNB-756.4 Mammary gland 13.0 CNS ca. (glio) SNB-19 4.4 Breast ca.* (pl.effusion) MCF-7 0.0 CNS ca. (glio) U251 4.2 Breast ca.* (pl. ef)MDA-MB-231 0.0 CNS ca. (glio) SF-295 0.0 Breast ca.* (pl. effusion) T47D0.0 Heart 61.1 Breast ca. BT-549 1.8 Skeletal Muscle (new lot*) 8.2Breast ca. MDA-N 0.0 Bone marrow 0.1 Ovary 10.2 Thymus 0.2 Ovarian ca.OVCAR-3 66.4 Spleen 0.0 Ovarian ca. OVCAR-4 1.3 Lymph node 5.1 Ovarianca. OVCAR-5 3.5 Colorectal 0.2 Ovarian ca. OVCAR-8 0.0 Stomach 5.9Ovarian ca. IGROV-1 0.3 Small intestine 11.8 Ovarian ca.* (ascites)SK-OV-3 0.0 Colon ca. SW480 0.0 Uterus 7.7 Colon ca.* (SW480 met) SW6202.7 Placenta 8.1 Colon ca. HT29 0.0 Prostate 4.6 Colon ca. HCT-116 0.0Prostate ca.* (bone met) PC-3 0.0 Colon ca. CaCo-2 0.5 Testis 4.6 83219CC Well to Mod Diff 0.5 Melanoma Hs688(A).T 0.0 (ODO3866) Colon ca.HCC-2998 0.0 Melanoma* (met) Hs688(B).T 0.0 Gastric ca.* (liver met)NCI- 0.0 Melanoma UACC-62 0.0 N87 Bladder 6.7 Melanoma M14 0.0 Trachea3.1 Melanoma LOX IMVI 0.0 Kidney 32.3 Melanoma* (met) SK-MEL-5 0.0Kidney (fetal) 51.8 Adipose 1.5

[0500] TABLE 30 Panel 2.2 Relative Relative Expression (%) Expression(%) Tissue Name 2.2x4tm6515f_ag1216_b1 Tissue Name2.2x4tm6515f_ag1216_b1 Normal Colon GENPAK 0.1 83793 Kidney NAT(OD04348) 11.6 061003 97759 Colon cancer (OD06064) 0.0 98938 Kidneymalignant cancer 0.0 (OD06204B) 97760 Colon cancer NAT 0.4 98939 Kidneynormal adjacent 1.4 (OD06064) tissue (OD06204E) 97778 Colon cancer(OD06159) 0.0 85973 Kidney Cancer 1.3 (OD04450-01) 97779 Colon cancerNAT 0.8 85974 Kidney NAT (OD04450- 3.2 (OD06159) 03) 98861 Colon cancer(OD06297- 0.0 Kidney Cancer Clontech 0.0 04) 8120613 98862 Colon cancerNAT 0.6 Kidney NAT Clontech 8120614 3.5 (OD06297-015) 83237 CC Gr. 2ascend colon 0.2 Kidney Cancer Clontech 3.5 (OD03921) 9010320 83238 CCNAT (ODO3921) 0.0 Kidney NAT Clontech 9010321 0.9 97766 Colon cancermetastasis 0.2 Kidney Cancer Clontech 8.3 (OD06104) 0.2 8120607 97767Lung NAT (OD06104) 1.1 Kidney NAT Clontech 8120608 0.7 87472 Colon metsto lung 0.3 Normal Uterus GENPAK 2.9 (OD04451-01) 061018 87473 Lun NAT(OD04451- 0.4 Uterus Cancer GENPAK 0.2 02) 064011 Normal ProstateClontech A + 0.5 Normal Thyroid Clontech A + 0.4 6546-1 (8090438) 6570-1(7080817) 84140 Prostate Cancer 0.2 Thyroid Cancer GENPAK 0.2 (OD04410)064010 84141 Prostate NAT 0.0 Thyroid Cancer INVITROGEN 0.3 (OD04410)A302152 Normal Ovary Res. Gen. 2.3 Thyroid NAT INVITROGEN 0.3 A30215398863 Ovarian cancer 4.6 Normal Breast GENPAK 1.3 (OD06283-03) 06101998865 Ovarian cancer 1.3 84877 Breast Cancer 0.4 NAT/fallopian tube(OD06283- (OD04566) 07) Ovarian Cancer GENPAK 9.7 Breast Cancer Res.Gen. 1024 0.4 064008 97773 Ovarian cancer 0.0 85975 Breast Cancer 1.6(OD06145) (OD04590-01) 97775 Ovarian cancer NAT 0.0 85976 Breast CancerMets 0.8 (OD06145) (OD04590-03) 98853 Ovarian cancer 0.2 87070 BreastCancer Metastasis 0.6 (OD06455-03) (OD04655-05) 98854 Ovarian NAT 1.9GENPAK Breast Cancer 0.9 (OD06455-07) Fallopian tube 064006 Normal LungGENPAK 061010 0.6 Breast Cancer Clontech 1.4 9100266 92337 Invasive poordiff. lung 0.4 Breast NAT Clontech 9100265 0.6 adeno (ODO4945-01 92338Lung NAT (ODO4945- 0.2 Breast Cancer INVITROGEN 0.0 03) A209073 84136Lung Malignant Cancer 0.0 Breast NAT INVITROGEN 1.4 A2090734 84137 LungNAT (OD03126) 0.4 97763 Breast cancer 0.8 (OD06083) 90372 Lung Cancer1.0 97764 Breast cancer node 0.9 (OD05014A) metastasis (OD06083) 90373Lung NAT (OD05014B) 2.1 Normal Liver GENPAK 0.3 061009 97761 Lung cancer(OD06081) 0.8 Liver Cancer Research Genetics 0.7 RNA 1026 97762 Lungcancer NAT 0.4 Liver Cancer Research Genetics 1.6 (OD06081) RNA 102585950 Lung Cancer (OD04237-01) 0.4 Paired Liver Cancer Tissue 0.0Research Genetics RNA 6004-T 85970 Lung NAT (OD04237-02) 0.0 PairedLiver Tissue Research 0.0 Genetics RNA 6004-N 83255 Ocular Mel Met toLiver 0.2 Paired Liver Cancer Tissue 1.3 (OD04310) Research Genetics RNA6005-T 83256 Liver NAT (OD04310) 0.0 Paired Liver Tissue Research 0.4Genetics RNA 6005-N 84139 Melanoma Mets to Lung 0.7 Liver Cancer GENPAK064003 0.5 (OD04321) 84138 Lung NAT (OD04321) 0.0 Normal Bladder GENPAK0.8 061001 Normal Kidney GENPAK 1.7 Bladder Cancer Research 0.7 061008Genetics RNA 1023 83786 Kidney Ca, Nuclear 5.3 Bladder Cancer INVITROGEN0.2 grade 2 (OD04338) A302173 83787 Kidney NAT (OD04338) 6.2 NormalStomach GENPAK 1.0 061017 83788 Kidney Ca Nuclear grade 100.0 GastricCancer Clontech 0.2 1/2 (OD04339) 9060397 83789 Kidney NAT (OD04339) 3.0NAT Stomach Clontech 0.4 9060396 83790 Kidney Ca. Clear cell 26.3Gastric Cancer Clontech 0.4 type (OD04340) 9060395 83791 Kidney NAT(OD04340) 0.9 NAT Stomach Clontech 0.7 9060394 83792 Kidney Ca. Nuclear5.1 Gastric Cancer GENPAK 1.1 grade 3 (OD04348) 064005

[0501] TABLE 31 Panel 4D Relative Expression (%) Tissue Name4Dtm2072f_ag1216 4Dtm2246f_ag1216 93768_Secondary Th1_anti-CD28/anti-CD30.0 0.0 93769_Secondary Th2_anti-CD28/anti-CD3 0.0 0.0 93770_SecondaryTr1_anti-CD28/anti-CD3 0.0 0.0 93573_Secondary Th1_resting day 4-6 inIL-2 0.0 0.0 93572_Secondary Th2_resting day 4-6 in IL-2 0.0 0.093571_Secondary Tr1_resting day 4-6 in IL-2 0.0 0.0 93568_primaryTh1_anti-CD28/anti-CD3 0.0 0.0 93569_primary Th2_anti-CD28/anti-CD3 0.00.0 93570_primary Tr1_anti-CD28/anti-CD3 0.0 0.0 93565_primaryTh1_resting dy 4-6 in IL-2 0.0 0.0 93566_primary Th2_resting dy 4-6 inIL-2 1.1 0.0 93567_primary Tr1_resting dy 4-6 in IL-2 0.0 0.993351_CD45RA CD4 lymphocyte_anti-CD28/anti-CD3 0.0 0.0 93352_CD45RO CD4lymphocyte_anti-CD28/anti-CD3 0.8 0.0 93251_CD8Lymphocytes_anti-CD28/anti-CD3 0.0 0.0 93353_chronic CD8 Lymphocytes2ry_resting dy 4-6 in IL-2 0.0 1.3 93574_chronic CD8 Lymphocytes2ry_activated CD3/CD28 0.0 0.0 93354_CD4_none 0.0 0.9 93252_SecondaryTh1/Th2/Tr1_anti-CD95 CH11 0.0 0.0 93103_LAK cells_resting 0.0 0.093788_LAK cells_IL-2 0.0 0.0 93787_LAK cells_IL-2 + IL-12 0.0 1.993789_LAK cells_IL-2 + IFN gamma 1.1 0.0 93790_LAK cells_IL-2 + IL-180.0 0.0 93104_LAK cells_PMA/ionomycin and IL-18 0.0 0.0 93578_NK CellsIL-2_resting 0.0 0.0 93109_Mixed Lymphocyte Reaction_Two Way MLR 0.0 0.093110_Mixed Lymphocyte Reaction_Two Way MLR 0.0 0.0 93111_MixedLymphocyte Reaction_Two Way MLR 0.0 0.0 93112_Mononuclear Cells(PBMCs)_resting 0.0 0.0 93113_Mononuclear Cells (PBMCs)_PWM 2.8 2.593114_Mononuclear Cells (PBMCs)_PHA-L 0.0 3.1 93249_Ramos (B cell)_none0.0 0.0 93250_Ramos (B cell)_ionomycin 0.0 0.0 93349_B lymphocytes_PWM0.0 0.0 93350_B lymphoytes_CD40L and IL-4 1.1 0.0 92665_EOL-1(Eosinophil)_dbcAMP differentiated 0.0 0.0 93248_EOL-1(Eosinophil)_dbcAMP/PMAionomycin 0.0 0.0 93356_Dendritic Cells_none 0.00.0 93355_Dendritic Cells_LPS 100 ng/ml 0.0 0.0 93775_DendriticCells_anti-CD40 0.0 0.0 93774_Monocytes_resting 0.0 0.093776_Monocytes_LPS 50 ng/ml 0.0 0.0 93581_Macrophages_resting 0.0 0.093582_Macrophages_LPS 100 ng/ml 0.8 0.0 93098_HUVEC (Endothelial)_none0.0 0.0 93099_HUVEC (Endothelial)_starved 0.0 0.0 93100_HUVEC(Endothelial)_IL-1b 0.0 1.3 93779_HUVEC (Endothelial)_IFN gamma 0.0 0.093102_HUVEC (Endothelial)_TNF alpha + IFN gamma 0.0 0.0 93101_HUVEC(Endothelial)_TNF alpha + IL4 0.0 0.0 93781_HUVEC (Endothelial)_IL-110.9 0.0 93583_Lung Microvascular Endothelial Cells_none 0.0 0.093584_Lung Microvascular Endothelial Cells_TNFa (4 ng/ml) 0.0 0.0 andIL1b (1 ng/ml) 92662_Microvascular Dermal endothelium_none 0.0 0.092663_Microvascular Dermal endothelium_TNFa (4 ng/ml) and 0.0 0.0 IL1b(1 ng/ml) 93773_Bronchial epithelium_TNFa (4 ng/ml) and IL1b (1 20.331.9 ng/ml)** 93347_Small Airway Epithelium_none 1.8 2.0 93348_SmallAirway Epithelium_TNFa (4 ng/ml) and IL1b (1 2.7 2.5 ng/ml)92668_Coronery Artery SMC_resting 0.0 0.0 92669_Coronery Artery SMC_TNFa(4 ng/ml) and IL1b (1 0.0 0.0 ng/ml) 93107_astrocytes_resting 12.8 16.393108_astrocytes_TNFa (4 ng/ml) and IL1b (1 ng/ml) 5.3 13.5 92666_KU-812(Basophil)_resting 0.0 0.0 92667_KU-812 (Basophil)_PMA/ionoycin 0.0 0.093579_CCD1106 (Keratinocytes)_none 1.4 0.0 93580_CCD1106(Keratinocytes)_TNFa and IFNg** 0.0 4.1 93791_Liver Cirrhosis 1.9 2.393792_Lupus Kidney 5.9 10.3 93577_NCI-H292 1.6 0.0 93358_NCI-H292_IL-40.7 0.0 93360_NCI-H292_IL-9 0.0 2.8 93359_NCI-H292_IL-13 0.0 0.093357_NCI-H292_IFN gamma 0.0 0.0 93777_HPAEC_ 0.0 0.0 93778_HPAEC_IL-1beta/TNA alpha 0.0 0.0 93254_Normal Human Lung Fibroblast_none 0.0 0.093253_Normal Human Lung Fibroblast_TNFa (4 ng/ml) and IL- 0.0 0.0 1b (1ng/ml) 93257_Normal Human Lung Fibroblast_IL-4 0.0 0.0 93256_NormalHuman Lung Fibroblast_IL-9 0.0 0.0 93255_Normal Human LungFibroblast_IL-13 0.0 0.0 93258_Normal Human Lung Fibroblast_IFN gamma0.0 0.0 93106_Dermal Fibroblasts CCD1070_resting 0.0 0.0 93361_DermalFibroblasts CCD1070_TNF alpha 4 ng/ml 0.0 0.0 93105_Dermal FibroblastsCCD1070_IL-1 beta 1 ng/ml 0.0 0.0 93772_dermal fibroblast_IFN gamma 0.00.0 93771_dermal fibroblast_IL-4 0.0 1.5 93259_IBD Colitis 1** 1.5 2.893260_IBD Colitis 2 0.0 1.2 93261_IBD Crohns 1.4 4.0 735010_Colon_normal3.4 2.7 735019_Lung_none 52.1 42.3 64028-1_Thymus_none 100.0 100.064030-1_Kidney_none 1.6 0.0

[0502] Panel 32. Panel CNSD.01 Relative Relative Expression (%)Expression (%) Tissue Name cns1x4tm6177f_ag1216_b2 Tissue Namecns1x4tm6177f_ag1216_(—b2) 102633_BA4 Control 18.7 102605_BA17 PSP 38.3102641_BA4 Control2 62.0 102612_BA17 PSP2 19.2 102625_BA4 Alzheimer's217.2 102637_Sub Nigra Control 6.8 102649_BA4 Parkinson's 79.4 102645_SubNigra Control2 12.2 102656_BA4 Parkinson's2 54.7 102629_Sub Nigra 10.8Alzheimer's2 102664_BA4 Huntington's 37.5 102660_Sub Nigra Parkinson's217.4 102671_BA4 Huntington's2 17.0 102667_Sub Nigra 21.1 Huntington's102603_BA4 PSP 16.5 102674_Sub Nigra 8.6 Huntington's2 102610_BA4 PSP222.9 102614_Sub Nigra PSP2 1.9 102588_BA4 Depression 45.0 102592_SubNigra Depression 1.9 102596_BA4 Depression2 27.0 102599_Sub NigraDepression2 3.6 102634_BA7 Control 45.2 102636_Glob Palladus Control21.2 102642_BA7 Control2 25.5 102644_Glob Palladus Control2 12.8102626_BA7 Alzheimer's2 20.0 102620_Glob Palladus 3.0 Alzheimer's102650_BA7 Parkinson's 48.1 102628_Glob Palladus 4.2 Alzheimer's2102657_BA7 Parkinson's2 27.3 102652_Glob Palladus 100.0 Parkinson's102665_BA7 Huntington's 58.5 102659_Glob Palladus 10.6 Parkinson's2102672_BA7 Huntington's2 65.1 102606_Glob Palladus PSP 4.3 102604_BA7PSP 93.8 102613_Glob Palladus PSP2 6.8 102611_BA7 PSP2 34.8 102591_GlobPalladus 9.1 Depression 102589_BA7 Depression 20.9 102638_Temp PoleControl 29.7 102632_BA9 Control 35.4 102646_Temp Pole Control2 63.9102640_BA9 Control2 58.7 102622_Temp Pole Alzheimer's 7.3 102617_BA9Alzheimer's 9.2 102630_Temp Pole 16.4 Alzheimer's2 102624_BA9Alzheimer's2 36.1 102653_Temp Pole Parkinson's 88.4 102648_BA9Parkinson's 33.0 102661_Temp Pole 50.2 Parkinson's2 102655_BA9Parkinson's2 32.2 102668_Temp Pole 63.5 Huntington's 102663_BA9Huntington's 50.4 102607_Temp Pole PSP 22.1 102670_BA9 Huntington's218.6 102615_Temp Pole PSP2 11.4 102602_BA9 PSP 14.3 102600_Temp Pole36.9 Depression2 102609_BA9 PSP2 7.6 102639_Cing Gyr Control 60.1102587_BA9 Depression 14.9 102647_Cing Gyr Control2 48.0 102595_BA9Depression2 18.3 102623_Cing Gyr Alzheimer's 19.4 102635_BA17 Control87.9 102631_Cing Gyr Alzheimer's2 24.8 102643_BA17 Control2 73.0102654_Cing Gyr Parkinson's 29.7 102627_BA17 Alzheimer's2 36.7102662_Cing Gyr Parkinson's2 33.2 102651_BA17 Parkinson's 81.0102669_Cing Gyr Huntington's 36.0 102658_BA17 Parkinson's2 95.4102676_Cing Gyr 27.7 Huntington's2 102666_BA17 Huntington's 78.7102608_Cing Gyr PSP 20.7 102673_BA17 Huntington's2 37.6 102616_Cing GyrPSP2 3.9 102590_BA17 Depression 33.7 102594_Cing Gyr Depression 34.6102597_BA17 Depression2 73.7 102601_Cing Gyr Depression2 21.0

[0503] Panel 1.2 Summary: Ag1216 The MOL4 gene is well expressed in avariety of normal tissues including kidney, heart, brain, thymus andlung. Of interest is the robust expression in activated endothelialcells, which may indicate that this gene is important for angiogenesisor lymphocyte trafficking. Inflammatory lymphocytes preferentiallytraffic into tissues by crossing activated endothelium. Expression ofthe MOL4 gene appears to be up regulated in renal cell carcinomas. Incontrast, expression of the MOMA gene is down regulated in a number ofcancer cell lines (including pancreatic, CNS, breast, and lung) relativeto the normal controls. No expression of this gene is detected in avariety of melanoma cell lines. Therefore, modulation of MOL4 genefunction may provide an effective treatment for a variety of cancers.

[0504] Panel 2.2 Summary: Ag1216 Expression of the MOL4 gene appears tobe associated with kidney cancers. This is in good agreement with thedata obtained in Panel 1.2 and suggests that therapeutic modulation ofthis gene using inhibitory monoclonal antibodies or small molecules mayprove useful in the treatment of kidney cancers. In addition, the MOL4gene may be a useful marker for the detection of renal cell carcinomas.

[0505] Panel 4D Summary: Ag1216 Two replicate experiments using the sameprobe and primer set were in good agreement. The MOL4 transcript ishighly expressed in thymus. To a much lesser degree, the transcript isalso expressed in the lung as well as in small airway epithelium treatedwith TNF-a and IL-1b. Therefore, protein therapeutics designed againstthe protein encoded for by this transcript could reduce inflammation inasthma or other lung disease such as emphysema.

[0506] Panel CNSD.01 Summary: Ag1216 Semaphorins can act as axonguidance proteins, specifically through their ability to act aschemorepellents that inhibit CNS regenerative capacity. Manipulation oflevels of the MOL4 semaphorin-like protein may therefore be of use ininducing a compensatory synaptogenic response to neuronal death inAlzheimer's disease, Parkinson's disease, Huntington's disease,spinocerebellar ataxia, progressive supranuclear palsy, multiplesclerosis, ALS, head trauma, stroke, or any other disease/conditionassociated with neuronal loss.

[0507] E. MOL5a

[0508] Expression of gene MOL5a was assessed using the primer-probe setsAg1215 and Ag1382 (identical sequences), described in Tables 33 and 34.Results of the RTQ-PCR runs are shown in Tables 35, 36, and 37. TABLE 33Probe Name Ag1215/Ag1382 Start Primers Sequences TM Length Position SEQID NO: Forward 5′-AACCCATTATCCTGCGTAACAT-3′ 59.6 22 619 80 Probe FAM-5′-68.5 26 645 81 CCCCACCACTCCATGAAGACAGAGTA-3′- TAMRA Reverse5′-CCTACAAAGTGAGGTTCGTTGA-3′ 59.3 22 685 82

[0509] TABLE 34 Panel 1.2 Relative Relative Expression (%) Expression(%) Tissue Name 1.2tm1403f_ag1215 1.2tm1581t_ag1382 Endothelial cells21.9 17.3 Endothelial cells (treated) 100.0 40.9 Pancreas 14.7 0.4Pancreatic ca. CAPAN2 3.4 0.7 Adrenal Gland (new lot*) 26.4 10.4 Thyroid18.8 0.3 Salivary gland 21.5 5.8 Pituitary gland 23.8 1.4 Brain (fetal)33.9 1.4 Brain (whole) 69.3 3.8 Brain (amygdala) 13.9 3.6 Brain(cerebellum) 67.4 3.0 Brain (hippocampus) 45.1 12.6 Brain (thalamus)19.1 26.4 Cerebral Cortex 53.2 30.1 Spinal cord 45.4 7.2 CNS ca.(glio/astro) U87-MG 7.8 21.3 CNS ca. (glio/astro) U-118-MG 6.8 13.5 CNSca. (astro) SW1783 2.0 1.8 CNS ca.* (neuro; met) SK-N-AS 50.3 27.5 CNSca. (astro) SF-539 20.3 21.2 CNS ca. (astro) SNB-75 13.7 2.8 CNS ca.(glio) SNB-19 19.5 28.9 CNS ca. (glio) U251 15.2 0.0 CNS ca. (glio)SF-295 15.0 5.1 Heart 63.3 12.2 Skeletal Muscle (new lot*) 27.7 0.8 Bonemarrow 2.9 0.9 Thymus 4.3 2.8 Spleen 33.4 15.6 Lymph node 23.7 5.4Colorectal 8.4 2.4 Stomach 36.3 9.6 Small intestine 27.9 11.7 Colon ca.SW480 6.1 1.8 Colon ca.* (SW480 met) SW620 10.4 40.3 Colon ca. HT29 3.02.5 Colon ca. HCT-116 6.9 11.0 Colon ca. CaCo-2 13.1 28.9 83219 CC Wellto Mod Diff (ODO3866) 3.1 1.8 Colon ca. HCC-2998 12.6 9.5 Gastric ca.*(liver met) NCI-N87 18.4 17.6 Bladder 40.1 15.5 Trachea 13.8 6.0 Kidney19.5 42.9 Kidney (fetal) 30.4 61.6 Renal ca. 786-0 6.1 6.7 Renal ca.A498 13.0 9.3 Renal ca. RXF 393 8.4 6.0 Renal ca. ACHN 10.7 4.9 Renalca. UO-31 8.8 3.6 Renal ca. TK-10 15.4 6.2 Liver 15.2 3.2 Liver (fetal)13.3 5.9 Liver ca. (hepatoblast) HepG2 21.8 12.1 Lung 19.3 0.7 Lung(fetal) 28.1 4.5 Lung ca. (small cell) LX-1 24.5 24.0 Lung ca. (smallcell) NCI-H69 8.1 12.7 Lung ca. (s. cell var.) SHP-77 3.8 1.8 Lung ca.(large cell) NCI-H460 40.3 19.5 Lung ca. (non-sm. cell) A549 13.1 13.9Lung ca. (non-s. cell) NCI-H23 28.1 24.5 Lung ca (non-s. cell) HOP-6242.3 9.7 Lung ca. (non-s. cl) NCI-H522 90.1 44.1 Lung ca. (squam.) SW900 37.4 57.8 Lung ca. (squam.) NCI-H596 9.8 4.2 Mammary gland 42.6 9.0Breast ca.* (pl. effusion) MCF-7 85.3 56.6 Breast ca.* (pl. ef)MDA-MB-231 5.3 1.4 Breast ca.* (pl. effusion) T47D 5.6 16.6 Breast ca.BT-549 5.0 2.6 Breast ca. MDA-N 16.7 3.7 Ovary 49.0 23.0 Ovarian ca.OVCAR-3 46.3 50.7 Ovarian ca. OVCAR-4 11.3 10.6 Ovarian ca. OVCAR-5 28.566.9 Ovarian ca. OVCAR-8 19.8 100.0 Ovarian ca. IGROV-1 18.2 13.3Ovarian ca.* (ascites) SK-OV-3 25.7 10.3 Uterus 24.5 3.5 Placenta 90.182.9 Prostate 28.5 15.0 Prostate ca.* (bone met) PC-3 39.0 15.4 Testis8.4 0.6 Melanoma Hs688(A).T 3.8 1.2 Melanoma* (met) Hs688(B).T 2.9 0.8Melanoma UACC-62 23.2 11.4 Melanoma M14 13.7 6.7 Melanoma LOX IMVI 9.61.8 Melanoma* (met) SK-MEL-5 27.4 8.9 Adipose 6.2 12.8

[0510] TABLE 35 Panel 2.2 Relative Relative Expression (%) Expression(%) Tissue Name 2.2x4tm6515f_ag1215_a2 Tissue Name2.2x4tm6515f_ag1215_a2 Normal Colon GENPAK 31.4 83793 Kidney NAT(OD04348) 39.7 061003 97759 Colon cancer (OD06064) 34.3 98938 Kidneymalignant cancer 15.4 (OD06204B) 97760 Colon cancer NAT 18.6 98939Kidney normal adjacent 10.4 (OD06064) tissue (OD06204E) 97778 Coloncancer (OD06159) 2.7 85973 Kidney Cancer 15.3 (OD04450-01 97779 Coloncancer NAT 22.5 85974 Kidney NAT (OD04450- 20.3 (OD06159) 03) 98861Colon cancer (OD06297- 3.2 Kidney Cancer Clontech 1.4 04) 8120613 98862Colon cancer NAT 30.6 Kidney NAT Clontech 8120614 20.3 (OD06297-015)83237 CC Gr. 2 ascend colon 11.6 Kidney Cancer Clontech 10.5 (ODO3921)9010320 83238 CC NAT (ODO3921) 8.4 Kidney NAT Clontech 9010321 9.0 97766Colon cancer metastasis 5.1 Kidney Cancer Clontech 32.2 (OD06104)8120607 97767 Lung NAT (OD06104) 8.3 Kidney NAT Clontech 8120608 12.187472 Colon mets to lung 15.3 Normal Uterus GENPAK 31.8 (OD04451-01)061018 87473 Lung NAT (OD04451- 4.3 Uterus Cancer GENPAK 31.4 02) 064011Normal Prostate Clontech A + 11.2 Normal Thyroid Clontech A+ 3.0 6546-1(8090438) 6570-1 (7080817) 84140 Prostate Cancer 10.0 Thyroid CancerGENPAK 14.8 (OD04410) 064010 84141 Prostate NAT 14.3 Thyroid CancerINVITROGEN 37.7 (OD04410) A302152 Normal Ovary Res. Gen. 74.7 ThyroidNAT INVITROGEN 7.0 A302153 98863 Ovarian cancer 27.6 Normal BreastGENPAK 35.4 (OD06283-03) 061019 98865 Ovarian cancer 6.4 84877 BreastCancer 15.6 NAT/fallopian tube (OD06283- (OD04566) 07) Ovarian CancerGENPAK 16.2 Breast Cancer Res. Gen. 1024 51.4 064008 97773 Ovariancancer 8.8 85975 Breast Cancer 36.8 (OD06145) (OD04590-01) 97775 Ovariancancer NAT 24.6 85976 Breast Cancer Mets 21.0 (OD06145) (OD04590-03)98853 Ovarian cancer 9.9 87070 Breast Cancer Metastasis 66.6(OD06455-03) (OD04655-05) 98854 Ovarian NAT 12.9 GENPAK Breast Cancer19.0 (OD06455-07) Fallopian tube 064006 Normal Lung GENPAK 061010 18.0Breast Cancer Clontech 27.7 9100266 92337 Invasive poor diff. lung 11.8Breast NAT Clontech 9100265 21.6 adeno (ODO4945-01 92338 Lung NAT(ODO4945- 13.8 Breast Cancer INVITROGEN 15.1 03) A209073 84136 LungMalignant Cancer 31.7 Breast NAT INVITROGEN 28.5 (OD03126) A209073484137 Lung NAT (OD03126) 5.6 97763 Breast cancer 100.0 (OD06083) 90372Lung Cancer 17.7 97764 Breast cancer node 64.9 (OD05014A) metastasis(OD06083) 90373 Lung NAT (OD05014B) 13.7 Normal Liver GENPAK 17.1 06100997761 Lung cancer (OD06081) 10.2 Liver Cancer Research Genetics 15.0 RNA1026 97762 Lung cancer NAT 8.2 Liver Cancer Research Genetics 36.3(OD06081) RNA 1025 85950 Lung Cancer (OD04237- 15.0 Paired Liver CancerTissue 18.1 01 Research Genetics RNA 6004-T 85970 Lung NAT (OD04237-24.0 Paired Liver Tissue Research 6.5 02) Genetics RNA 6004-N 83255Ocular Mel Met to Liver 25.5 Paired Liver Cancer Tissue 33.3 (OD04310)Research Genetics RNA 6005-T 83256 Liver NAT (OD04310) 18.1 Paired LiverTissue Research 31.6 Genetics RNA 6005-N 84139 Melanoma Mets to Lung41.3 Liver Cancer GENPAK 064003 8.9 (OD04321) 84138 Lung NAT (OD04321)9.1 Normal Bladder GENPAK 14.7 061001 Normal Kidney GENPAK 7.5 BladderCancer Research 6.0 061008 Genetics RNA 1023 83786 Kidney Ca, Nuclear34.7 Bladder Cancer INVITROGEN 28.9 grade 2 (OD04338) A302173 83787Kidney NAT (OD04338) 7.6 Normal Stomach GENPAK 33.6 061017 83788 KidneyCa Nuclear grade 38.3 Gastric Cancer Clontech 3.6 1/2 (OD04339) 906039783789 Kidney NAT (OD04339) 6.8 NAT Stomach Clontech 12.2 9060396 83790Kidney Ca, Clear cell 19.2 Gastric Cancer Clontech 15.1 type (OD04340)9060395 83791 Kidney NAT (OD04340) 18.7 NAT Stomach Clontech 21.29060394 83792 Kidney Ca, Nuclear 10.4 Gastric Cancer GENPAK 17.4 grade 3(OD04348) 064005

[0511] Panel 36. Panel 4D Relative Relative Expression (%) Expression(%) Tissue Name 4Dtm2070f_ag1215 4Dtin2425t_ag1382 93768_SecondaryTh1_anti-CD28/anti-CD3 27.9 19.6 93769_Secondary Th2_anti-CD28/anti-CD335.4 25.5 93770_Secondary Tr1_anti-CD28/anti-CD3 42.0 37.693573_Secondary Th1_resting day 4-6 in IL-2 29.5 18.8 93572_SecondaryTh2_resting day 4-6 in IL-2 27.5 21.9 93571_Secondary Tr1_resting day4-6 in IL-2 33.7 23.2 93568_primary Th1_anti-CD28/anti-CD3 35.1 28.193569_primary Th2_anti-CD28/anti-CD3 31.4 25.7 93570_primaryTr1_anti-CD28/anti-CD3 55.9 42.6 93565_primary Th1_resting dy 4-6 inIL-2 91.4 100.0 93566_primary Th2_resting dy 4-6 in IL-2 68.8 64.693567_primary Tr1_resting dy 4-6 in IL-2 55.5 52.1 93351_CD45RA CD4lymphocyte_anti-CD28/anti-CD3 21.6 17.8 93352_CD45RO CD4lymphocyte_anti-CD28/anti-CD3 24.5 17.2 93251_CD8Lymphocytes_anti-CD28/anti-CD3 22.1 15.5 93353_chronic CD8 Lymphocytes2ry_resting dy 4-6 in IL-2 17.1 12.4 93574_chronic CD8 Lymphocytes2ry_activated CD3/CD28 29.7 18.2 93354_CD4_none 17.9 15.493252_Secondary Th1/Th2/Tr1_anti-CD95 CH11 71.7 67.4 93103_LAKcells_resting 17.1 10.3 93788_LAK cells_IL-2 21.5 15.7 93787_LAKcells_IL-2 + IL-12 18.4 17.1 93789_LAK cells_IL-2 + IFN gamma 29.5 22.293790_LAK cells_IL-2 + IL-18 18.0 22.1 93104_LAK cells_PMA/ionomycin andIL-18 10.7 7.3 93578_NK Cells IL-2_resting 31.9 17.2 93109_MixedLymphocyte Reaction_Two Way MLR 9.5 7.6 93110_Mixed LymphocyteReaction_Two Way MLR 6.2 6.8 93111_Mixed Lymphocyte Reaction_Two Way MLR10.5 8.5 93112_Mononuclear Cells (PBMCs)_resting 10.7 10.393113_Mononuclear Cells (PBMCs)_PWM 50.7 38.4 93114_Mononuclear Cells(PBMCs)_PHA-L 32.5 31.2 93249_Ramos (B cell)_none 0.0 0.0 93250_Ramos (Bcell)_ionomycin 0.0 0.0 93349_B lymphocytes_PWM 36.1 34.2 93350_Blymphoytes_CD40L and IL-4 18.3 17.2 92665_EOL-1 (Eosinophil)_dbcAMPdifferentiated 43.8 30.1 93248_EOL-1 (Eosinophil)_dbcAMP/PMAionomycin73.2 63.7 93356_Dendritic Cells_none 1.6 0.6 93355_Dendritic Cells LPS100 ng/ml 1.2 5.0 93775_Dendritic Cells_anti-CD40 0.9 0.993774_Monocytes_resting 2.9 1.8 93776_Monocytes_LPS 50 ng/ml 29.7 19.293581_Macrophages_resting 4.9 2.3 93582_Macrophages_LPS 100 ng/ml 7.24.4 93098_HUVEC (Endothelial)_none 9.2 6.5 93099_HUVEC(Endothelial)_starved 18.6 14.7 93100_HUVEC (Endothelial)_IL-1b 3.9 2.693779_HUVEC (Endothelial)_IFN gamma 19.2 17.1 93102_HUVEC(Endothelial)_TNF alpha + IFN gamma 2.1 2.4 93101_HUVEC(Endothelial)_TNF alpha + IL4 15.3 12.2 93781_HUVEC (Endothelial)_IL-1113.6 15.3 93583_Lung Microvascular Endothelial Cells_none 19.9 20.493584_Lung Microvascular Endothelial Cells_TNFa (4 ng/ml) 18.0 14.9 andIL1b (1 ng/ml) 92662_Microvascular Dermal endothelium_none 29.7 26.892663_Microsvasular Dermal endothelium_TNFa (4 ng/ml) and 36.9 33.4 IL1b(1 ng/ml) 93773_Bronchial epithelium_TNFa (4 ng/ml) and IL1b (1 41.525.7 ng/ml)** 93347_Small Airway Epithelium_none 13.3 8.8 93348_SmallAirway Epithelium_TNFa (4 ng/ml) and IL1b (1 56.6 45.4 ng/ml)92668_Coronery Artery SMC_resting 22.2 19.8 92669_Coronery ArterySMC_TNFa (4 ng/ml) and IL1b (1 28.1 19.9 ng/ml) 93107_astrocytes_resting13.0 20.2 93108_astrocytes_TNFa (4 ng/ml) and IL1b (1 ng/ml) 23.7 18.692666_KU-812 (Basophil)_resting 97.3 75.3 92667_KU-S 12(Basophil)_PMA/ionoycin 100.0 90.1 93579_CCD1106 (Keratinocytes)_none16.6 13.8 93580_CCD1106 (Keratinocytes)_TNFa and IFNg** 67.8 11.393791_Liver Cirrhosis 14.3 12.3 93792_Lupus Kidney 28.7 18.893577_NCI-H292 27.4 28.3 93358_NCI-H292_IL-4 61.1 55.193360_NCI-H292_IL-9 37.6 31.6 93359_NCI-H292_IL-13 44.4 42.993357_NCI-H292_IFN gamma 21.0 20.3 93777_HPAEC_ 21.5 17.293778_HPAEC_IL-1 beta/TNA alpha 11.0 9.5 93254_Normal Human LungFibroblast_none 31.0 20.6 93253_Normal Human Lung Fibroblast_TNFa (4ng/ml) and IL- 26.1 23.5 1b (1 ng/ml) 93257_Normal Human LungFibroblast_IL-4 40.6 37.1 93256_Normal Human Lung Fibroblast_IL-9 21.317.7 93255_Normal Human Lung Fibroblast_IL-13 56.3 53.2 93258_NormalHuman Lung Fibroblast_IFN gamma 59.5 45.4 93106_Dermal FibroblastsCCD1070_resting 47.0 33.4 93361_Dermal Fibroblasts CCD1070_TNF alpha 4ng/ml 73.7 55.1 93105_Dermal Fibroblasts CCD1070_IL-1 beta 1 ng/ml 36.637.4 93772_dermal fibroblast_IFN gamma 8.8 9.7 93771_dermalfibroblast_IL-4 20.2 19.6 93259_IBD Colitis 1** 13.2 10.7 93260_IBDColitis 2 4.1 2.0 93261_IBD Crohns 3.1 3.1 735010_Colon_normal 29.9 24.3735019_Lung_none 46.0 38.4 64028-1_Thymus_none 60.3 54.064030-1_Kidney_none 32.1 26.4

[0512] TABLE 37 Panel CNSD.01 Relative Relative Expression (%)Expression (%) Tissue Name cns1x4tm6177f_ag1215_b1 Tissue Namecns1x4tm6177f_ag1215_b1 102633_BA4 Control 20.2 102605_BA17 PSP 31.1102641_BA4 Control2 34.5 102612_BA17 PSP2 9.9 102625_BA4 Alzheimer's29.0 102637_Sub Nigra Control 54.5 102649_BA4 Parkinson's 32.9 102645_SubNigra Control2 31.7 102656_BA4 Parkinson's2 46.8 102629_Sub Nigra 24.2Alzheimer's2 102664_BA4 Huntington's 36.2 102660_Sub Nigra Parkinson's291.5 102671_BA4 Huntington's2 11.1 102667_Sub Nigra 80.6 Huntington's102603_BA4 PSP 15.8 102674_Sub Nigra 43.0 Huntington's2 102610_BA4 PSP245.9 102614_Sub Nigra PSP2 24.8 102588_BA4 Depression 19.6 1025925_SubNigra Depression 18.5 102596_BA4 Depression 27.8 102599_Sub NigraDepression2 12.0 102634_BA7 Control 26.1 102636_Glob Palladus Control20.2 102642_BA7 Control2 32.8 102644_Glob Palladus Control2 10.7102626_BA7 Alzheimer's2 4.5 102620_Glob Palladus 21.6 Alzheimer's102650_BA7 Parkinson's 22.9 102628_Glob Palladus 4.9 Alzheimer's2102657_BA7 Parkinson's2 35.5 102652_Glob Palladus 100.0 Parkinson's102665_BA7 Huntington's 39.1 102659_Glob Palladus 23.0 Parkinson's2102672_BA7 Huntington's2 40.4 102606_Glob Palladus PSP 10.1 102604_BA7PSP 31.2 102613_Glob Palladus PSP2 11.8 102611_BA7 PSP2 32.2 102591_GlobPalladus 23.4 Depression 102589_BA7 Depression 6.2 102638_Temp PoleControl 7.7 102632_BA9 Control 12.5 102646_Temp Pole Control2 29.2102640_BA9 Control2 48.5 102622_Temp Pole Alzheimer's 4.0 102617_BA9Alzheimer's 6.9 102630_Temp Pole 3.6 Alzheimer's2 102624_BA9Alzheimer's2 5.4 102653_Temp Pole Parkinson's 22.5 102648_BA9Parkinson's 25.2 102661_Temp Pole 22.1 Parkinson's2 102655_BA9Parkinson's2 33.4 102668_Temp Pole 30.6 Huntington's 102663_BA9Huntington's 44.8 102607_Temp Pole PSP 3.8 102670_BA9 Huntington's2 13.7102615_Temp Pole PSP2 2.2 102602_BA9 PSP 23.4 102600_Temp Pole 7.1Depression2 102609_BA9 PSP2 5.0 102639_Cing Gyr Control 58.9 102587_BA9Depression 10.8 102647_Cing Gyr Control2 40.2 102595_BA9 Depression211.8 102623_Cing Gyr Alzheimer's 19.3 102635_BA17 Control 39.6102631_Cing GyrAlzheimer's2 11.8 102643_BA17 Control2 40.0 102654_CingGyr Parkinson's 42.1 102627_BA17 Alzheimer's2 7.6 102662 Cing GyrParkinson's2 35.7 102651_BA17 Parkinson's 31.2 102669_Cing GyrHuntington's 62.0 102658_BA17 Parkinson's2 35.2 102676_Cing Gyr 28.7Huntington's2 102666_BA17 Huntington's 47.2 102608_Cing Gyr PSP 66.8102673_BA17 Huntington's2 25.0 102616_Cing Gyr PSP2 5.2 102590_BA17Depression 22.2 102594_Cing Gyr Depression 14.7 102597_BA17 Depression241.7 102601_Cing Gyr Depression2 32.0

[0513] Panel 1.2 Summary: Ag1215/Ag1382 Two replicate experiments wereperformed using probe and primer sets of identical sequences; however,relatively disparate results were obtained on this panel. For Ag1215,the MOL5a gene is expressed at high levels across most of the tissues onthis panel with highest expression in treated endothelial cells (CTvalue=23). For Ag1382, the MOL5a gene is expressed at high levels acrossmost of the tissues on this panel with highest expression in an ovariancancer cell line (CT value=22). To summarize the expression profile,there appears to be widespread expression of the MOL5a gene in a numberof tissues and cell lines. Furthermore, the expression of this geneseems to be associated with reproductive tissues and cancer cell lineswhose origins are such. For instance, there is significant expression inovarian cell lines, breast cell lines and placenta tissue. There is alsomoderate expression in kidney tissues and lung cell lines.

[0514] Panel 2.2 Summary: Ag1215 There appears to be widespreadexpression of the MOL5a gene in the samples of panel 2.2. Specifically,there seems to be an association of expression in breast cancer andnormal ovarian tissue. This is reasonably consistent with the resultsobtained from Panel 1.2. In addition, there is also some correlationwith expression in normal kidney tissue when compared to kidney cancers,also consistent with the observations in Panel 1.2.

[0515] Thus, therapeutic modulation of this gene or gene product mightshow utility in the treatmnent of breast cancer, ovarian cancer orkidney cancer. Panel 4D Summary: Ag1215/Ag1382 Results from tworeplicate experiments performed using probe and primer sets of identicalsequences are in reasonable agreement. The MOL5a transcript is widelyexpressed in cell lines from this panel (CT values 25-30), includingthymus, lung, muco-epidermoid cell lines, fibroblasts from diverseorigin, and activated T cells. In addition, the MOL5a gene is expressedin normal colon but not in colons from patients with Crohn's disease orcolitis. Thus, protein therapeutics designed with the putativesemaphorin encoded for by this protein could reduce or eliminateinflammation and tissue destruction due to IBD. High expression of thistranscript was found on primary resting Th1 T cells, and also primaryresting Th2 and Tr1 T cells. The high expression of this transcript insecondary T cells treated with CD95 suggests that this transcriptencodes for a protein involved in activation of cell death. Furthermore,high expression of the MOL5A transcript is also found in activatedbasophils and eosinophils, suggesting a role for this protein inallergic disorder such as asthma, contact hypersensitivity, andhypersensitive immediate reactions. Antibody or protein therapeuticsdesigned against the protein encoded for by this transcript couldtherefore reduce or inhibit inflammation in allergy, asthma, emphysema,psoriasis and/or autoimmunity.

[0516] Panel CNSD.01 Summary: Ag1215 Semaphorins can act as axonguidance proteins, specifically through their ability to act aschemorepellents that inhibit CNS regenerative capacity. Manipulation oflevels of the MOL4 semaphorin-like protein may therefore be of use ininducing a compensatory synaptogenic response to neuronal death inAlzheimer's disease, Parkinson's disease, Huntington's disease,spinocerebellar ataxia, progressive supranuclear palsy, multiplesclerosis, ALS, head trauma, stroke, or any other disease/conditionassociated with neuronal loss.

Example 2 TaqMan Data for MOL7

[0517] TaqMan data was acquired for MOL7 as described in Example 1 usingthe primers specified. The relative expression of MOL7 in the describedtissues is represented in the graphs below.

Example 3 SeqCallingTM Technology

[0518] cDNA was derived from various human samples representing multipletissue types, normal and diseased states, physiological states, anddevelopmental states from different donors. Samples were obtained aswhole tissue, cell lines, primary cells or tissue cultured primary cellsand cell lines. Cells and cell lines may have been treated withbiological or chemical agents that regulate gene expression for example,growth factors, chemokines, steroids. The cDNA thus derived was thensequenced using CuraGen's proprietary SeqCalling technology. Sequencetraces were evaluated manually and edited for corrections ifappropriate. cDNA sequences from all samples were assembled withthemselves and with public ESTs using bioinformatics programs togenerate CuraGen's human SeqCalling database of SeqCalling assemblies.Each assembly contains one or more overlapping cDNA sequences derivedfrom one or more human samples. Fragments and ESTs were included ascomponents for an assembly when the extent of identity with anothercomponent of the assembly was at least 95% over 50 bp. Each assembly canrepresent a gene and/or its variants such as splice forms and/or singlenucleotide polymorphisms (SNPs) and their combinations.

[0519] Variant sequences are included in this application. A variantsequence can include a single nucleotide polymorphism (SNP). A SNP can,in some instances, be referred to as a “cSNP” to denote that thenucleotide sequence containing the SNP originates as a cDNA. A SNP canarise in several ways. For example, a SNP may be due to a substitutionof one nucleotide for another at the polymorphic site. Such asubstitution can be either a transition or a transversion. A SNP canalso arise from a deletion of a nucleotide or an insertion of anucleotide, relative to a reference allele. In this case, thepolymorphic site is a site at which one allele bears a gap with respectto a particular nucleotide in another allele. SNPs occurring withingenes may result in an alteration of the amino acid encoded by the geneat the position of the SNP. Intragenic SNPs may also be silent, however,in the case that a codon including a SNP encodes the same amino acid asa result of the redundancy of the genetic code. SNPs occurring outsidethe region of a gene, or in an intron within a gene, do not result inchanges in any amino acid sequence of a protein but may result inaltered regulation of the expression pattern for example, alteration intemporal expression, physiological response regulation, cell typeexpression regulation, intensity of expression, stability of transcribedmessage.

[0520] Method of novel SNP Identification: SNPs are identified byanalyzing sequence assemblies using CuraGen's proprietary SNPToolalgorithm. SNPTool identifies variation in assemblies with the followingcriteria: SNPs are not analyzed within 10 base pairs on both ends of analignment; Window size (number of bases in a view) is 10; The allowednumber of mismatches in a window is 2; Minimum SNP base quality (PHREDscore) is 23; Minimum number of changes to score an SNP is 2/assemblyposition. SNPTool analyzes the assembly and displays SNP positions,associated individual variant sequences in the assembly, the depth ofthe assembly at that given position, the putative assembly allelefrequency, and the SNP sequence variation. Sequence traces are thenselected and brought into view for manual validation. The consensusassembly sequence is imported into CuraTools along with variant sequencechanges to identify potential amino acid changes resulting from the SNPsequence variation. Comprehensive SNP data analysis is then exportedinto the SNPCalling database.

[0521] Method of novel SNP Confirmation: SNPs are confirmed employing avalidated method know as Pyrosequencing (Pyrosequencing, Westborough,Mass.). Detailed protocols for Pyrosequencing can be found in:

[0522] Alderborn et al. Determination of Single Nucleotide Polymorphismsby Real-time Pyrophosphate DNA Sequencing. (2000). Genome Research. 10,Issue 8, August. 1249-1265.

[0523] In brief, Pyrosequencing is a real time primer extension processof genotyping. This protocol takes double-stranded, biotinylated PCRproducts from genomic DNA samples and binds them to streptavidin beads.These beads are then denatured producing single stranded bound DNA. SNPsare characterized utilizing a technique based on an indirectbioluminometric assay of pyrophosphate (PPi) that is released from eachdNTP upon DNA chain elongation. Following Klenow polymerase-mediatedbase incorporation, PPi is released and used as a substrate, togetherwith adenosine 5′-phosphosulfate (APS), for ATP sulfurylase, whichresults in the formation of ATP. Subsequently, the ATP accomplishes theconversion of luciferin to its oxi-derivative by the action ofluciferase. The ensuing light output becomes proportional to the numberof added bases, up to about four bases. To allow processivity of themethod dNTP excess is degraded by apyrase, which is also present in thestarting reaction mixture, so that only dNTPs are added to the templateduring the sequencing. The process has been fully automated and adaptedto a 96-well format, which allows rapid screening of large SNP panels.

EQUIVALENTS

[0524] Although particular embodiments have been disclosed herein indetail, this has been done by way of example for purposes ofillustration only, and is not intended to be limiting with respect tothe scope of the appended claims, which follow. In particular, it iscontemplated by the inventors that various substitutions, alterations,and modifications may be made to the invention without departing fromthe spirit and scope of the invention as defined by the claims. Thechoice of nucleic acid starting material, clone of interest, or librarytype is believed to be a matter of routine for a person of ordinaryskill in the art with knowledge of the embodiments described herein.Other aspects, advantages, and modifications considered to be within thescope of the following claims.

1 100 1 7410 DNA Homo sapiens 1 atgcccgccc tgcgccccgc tctgctgtgggcgctgctgg cgctctggct gtgctgcgcg 60 acccccgcgc atgcattgca gtgtcgagatggctatgaac cctgtgtaaa tgaaggaatg 120 tgtgttacct accacaatgg cacaggatactgcaaatgtc cagaaggctt cttgggggaa 180 tattgtcaac atcgagaccc ctgtgagaagaaccgctgcc agaatggtgg gacttgtgtg 240 gcccaggcca tgctggggaa agccacgtgccgatgtgcct cagggtttac aggagaggac 300 tgccagtact cgacatctca tccatgctttgtgtctcgac cttgcctgaa tggcggcaca 360 tgccatatgc tcagccggga tacctatgagtgcacctgtc aagtcgggtt tacaggtaag 420 gagtgccaat ggacggatgc ctgcctgtctcatccctgtg caaatggaag tacctgtacc 480 actgtggcca accagttctc ctgcaaatgcctcacaggct tcacagggca gaaatgtgag 540 actgatgtca atgagtgtga cattccaggacactgccagc atggtggcac ctgcctcaac 600 ctgcctggtt cctaccagtg ccagtgccctcagggcttca caggccagta ctgtgacagc 660 ctgtatgtgc cctgtgcacc ctcaccttgtgtcaatggag gcacctgtcg gcagactggt 720 gacttcactt ttgagtgcca tttaccaggttttgaaggga gcacctgtga gaggaatatt 780 gatgactgcc ctaaccacag gtgtcagaatggaggggttt gtgtggatgg ggtcaacact 840 tacaactgcc gctgtccccc acaatggacaggacagttct gcacagagga tgtggatgaa 900 tgcctgctgc agcccaatgc ctgtcaaaactggggcacct gtgccaaccg caatggaggc 960 tatggctgtg tatgtgtcaa cggctggagtggagatgact gcagtgagaa cattgatgat 1020 tgtgctttcg gcgcctgtac tccaggctccacctgcatcg accgtgtggc ctccttctct 1080 tgcatgtgcc cagaggggaa ggcaggtctcctgtgtcatc tggatgatgc atgcatcagc 1140 aatccttgcc acaagggggc actgtgtgacaccaaccccc taaatgggca atatatttgc 1200 acctgcccac aaggctacaa aggggctgactgcacagaag atgtggatga atgtgccatg 1260 gccaatagca atccttgtga gcatgcaggaaaatgtgtga acacggatgg cgccttccac 1320 tgtgagtgtc tgaagggtta tgcaggacctcgttgtgaga tggacatcaa tgagtgccat 1380 tcagacccct gccagaatga tgctacctgtctggataaga ttggaggctt cacatgtctg 1440 tgcatgccag gtttcaaagg tgtgcattgtgaattagaaa taaatgaatg tcagagcaac 1500 ccttgtgtga acaatgggca gtgtgtggataaagtcaatc gtttccagtg cctgtgtcct 1560 cctggtttca ctgggccagt ttgccagattgatattgatg actgttccag tactccgtgt 1620 ctgaatgggg caaagtgtat cgatcacccgaatggctatg aatgccagtg tgccacaggt 1680 ttcactggtg tgttgtgtga ggagaacattgacaactgtg accccgatcc ttgccaccat 1740 ggtcagtgtc aggatggtat tgattcctacacctgcatct gcaatcccgg gtacatgggc 1800 gccatctgca gtgaccagat tgatgaatgttacagcagcc cttgcctgaa cgatggtcgc 1860 tgcattgacc tggtcaatgg ctaccagtgcaactgccagc caggcacgtc aggtgttaat 1920 tgtgaaatta attttgatga ctgtgcaagtaacccttgta tccatggaat ctgtatggat 1980 ggcattaatc gctacagttg tgtctgctcaccaggattca cagggcagag atgtaacatt 2040 gacattgatg agtgtgcctc caatccctgtcgcaagggtg caacatgtat caacggtgtg 2100 aatggtttcc gctgtatatg ccccgagggaccccatcacc ccagctgcta ctcacaggtg 2160 aacgaatgcc tgagcaatcc ctgcatccatggaaactgta ctggaggtct cagtggatat 2220 aagtgtctct gtgatgcagg ctgggttggcatcaactgtg aagtggacaa aaatgaatgc 2280 ctttcgaatc catgccagaa tggaggaacttgtgacaatc tggtgaatgg atacaggtgt 2340 acttgcaaga agggctttaa aggctataactgccaggtga atattgatga atgtgcctca 2400 aatccatgcc tgaaccaagg aacctgctttgatgacataa gtggctacac ttgccactgt 2460 gtgctgccat acacaggtaa gaattgtcagacagtattgg ctccctgttc cccaaaccct 2520 tgtgagaatg ctgctgtttg caaagagtcaccaaattttg agagttatac ttgcttgtgt 2580 gctcctggct ggcaaggtca gcggtgtaccattgacattg acgagtgtat ctccaagccc 2640 tgcatgaacc atggtctctg ccataacacccagggcagct acatgtgtga atgtccacca 2700 ggcttcagtg gtatggactg tgaggaggacattgatgact gccttgccag tccttgccag 2760 aatggaggtt cctgtatgga tggagtgaatactttctcct gcctctgcct tccgggtttc 2820 actggggata agtgccagac agacatgaatgagtgtctga gtgaaccctg taagaatgga 2880 gggacctgct ctgactacgt caacagttacacttgcaagt gccaggcagg atttgatgga 2940 gtccattgtg agaacaacat caatgagtgcactgagagct cctgtttcaa tggtggcaca 3000 tgtgttgatg ggattaactc cttctcttgcttgtgccctg tgggtttcac tggatccttc 3060 tgcctccatg agatcaatga atgcagctctcatccatgcc tgaatgatgg aacgtgtgtt 3120 gatggcctgg gtacctaccg ctgcagctgccccctgggct acactgggaa aaactgtcag 3180 accctggtga atctctgcag tcggtctccatgtaaaaaca aaggtacttg cgttcagaaa 3240 aaagcagagt cccagtgcct atgtccatctggatgggctg gtgcctattg tgacgtgccc 3300 aatgtctctt gtgacatagc agcctccaggagaggtgtgc ttgttgaaca cttgtgccag 3360 cactcaggtg tctgcatcaa tgctggcaacacgcattact gtcagtgccc cctgggctat 3420 actgggagct actgtgagga gcaactcgatgagtgtgcgt ccaacccctg ccagcacggg 3480 gcaacatgca gtgacttcat tggtggatacagatgcgagt gtgtcccagg ctatcagggt 3540 gtcaactgtg agtatgaagt ggatgagtgccagaatcagc cctgccagaa tggaggcacc 3600 tgtattgacc ttgtgaacca tttcaagtgctcttgcccac caggcactcg gggtatgaaa 3660 tcatccttat ccattttcca ttgcccgggtccccattgcc ttaatggtgg tcagtgcatg 3720 gataggattg gaggctacag ttgtcgctgcttgcctggct ttgctgggga gcgttgtgag 3780 ggagacatca acgagtgcct ctccaacccctgcagctctg agggcagcct ggactgtata 3840 cagctcacca atgactacct gtgtgtttgccgtagtgcct ttactggtcg gcactgtgaa 3900 accttcgtcg atgtgtgtcc ccagatgccctgcctgaatg gagggacttg tgctgtggcc 3960 agtaacatgc ctgatggttc atttgccgttgtcccccagg gattttccgg ggcaaggtgc 4020 cagagcagct gtggacaagt gaaatgtaggaagggggagc agtgtgtgca caccgcctct 4080 ggaccccgct gcttctgccc cagtccccgggactgcgagt caggctgtgc cagtagcccc 4140 tgccagcacg ggggcagctg ccaccctcagcgccagcctc cttattactc ctgccagtgt 4200 gccccaccat tctcgggtag ccgctgtgaactctacacgg caccccccag cacccctcct 4260 gccacctgtc tgagccagta ttgtgccgacaaagctcggg atggcgtctg tgatgaggcc 4320 tgcaacagcc atgcctgcca gtgggatgggggtgactgtt ctctcaccat ggagaacccc 4380 tgggccaact gctcctcccc acttccctgctgggattata tcaacaacca gtgtgatgag 4440 ctgtgcaaca cggtcgagtg cctgtttgacaactttgaat gccaggggaa cagcaagaca 4500 tgcaagtatg acaaatactg tgcagaccacttcaaagaca accactgtga ccaggggtgc 4560 aacagtgagg agtgtggttg ggatgggctggactgtgctg ctgaccaacc tgagaacctg 4620 gcagaaggta ccctggttat tgtggtattgatgccacctg aacaactgct ccaggatgct 4680 cgcagcttct tgcgggcact gggtaccctgctccacacca acctgcgcat taagcgggac 4740 tcccaggggg aactcatggt gtacccctattatggtgaga agtcagctgc tatgaagaaa 4800 cagaggatga cacgcagatc ccttcctggtgaacaagaac aggaggtggc tgggtctaaa 4860 gtctttctgg aaattgacaa ccgccagtgtgttcaagact cagaccactg cttcaagaac 4920 acggatgcag cagcagctct cctggcctctcacgccatac aggggaccct gtcataccct 4980 cttgtgtctg tcgtcagtga gtccctgactccagaacgca ctcagctcct ctatctcctt 5040 gctgttgctg ttgtcatcat tctgtttattattctgctgg gggtaatcat ggcaaaacga 5100 aagcgtaagc atggctctct ctggctgcctgaaggtttca ctcttcgccg agatgcaagc 5160 aatcacaagc gtcgtgagcc agtgggacaggatgctgtgg ggctgaaaaa tctctcagtg 5220 caagtctcag aagctaacct aattggtactggaacaagtg aacactgggt cgatgatgaa 5280 gggccccagc caaagaaagt aaaggctgaagatgaggcct tactctcaga agaagatgac 5340 cccattgatc gacggccatg gacacagcagcaccttgaag ctgcagacat ccgtaggaca 5400 ccatcgctgg ctctcacccc tcctcaggcagagcaggagg tggatgtgtt agatgtgaat 5460 gtccgtggcc cagatggctg caccccattgatgttggctt ctctccgagg aggcagctca 5520 gatttgagtg atgaagatga agatgcagaggactcttctg ctaacatcat cacagacttg 5580 gtctaccagg gtgccagcct ccaggcccagacagaccgga ctggtgagat ggccctgcac 5640 cttgcagccc gctactcacg ggctgatgctgccaagcgtc tcctggatgc aggtgcagat 5700 gccaatgccc aggacaacat gggccgctgtccactccatg ctgcagtggc agctgatgcc 5760 caaggtgtct tccagattct gattcgcaaccgagtaactg atctagatgc caggatgaat 5820 gatggtacta cacccctgat cctggctgcccgcctggctg tggagggaat ggtggcagaa 5880 ctgatcaact gccaagcgga tgtgaatgcagtggatgacc atggaaaatc tgctcttcac 5940 tgggcagctg ctgtcaataa tgtggaggcaactcttttgt tgttgaaaaa tggggccaac 6000 cgagacatgc aggacaacaa ggaagagacacctctgtttc ttgctgcccg ggaggggagc 6060 tatgaagcag ccaagatcct gttagaccattttgccaatc gagacatcac agaccatatg 6120 gatcgtcttc cccgggatgt ggctcgggatcgcatgcacc atgacattgt gcgccttctg 6180 gatgaataca atgtgacccc aagccctccaggcaccgtgt tgacttctgc tctctcacct 6240 gtcatctgtg ggcccaacag atctttcctcagcctgaagc acaccccaat gggcaagaag 6300 tctagacggc ccagtgccaa gagtaccatgcctactagcc tccctaacct tgccaaggag 6360 gcaaaggatg ccaagggtag taggaggaagaagtctctga gtgagaaggt ccaactgtct 6420 gagagttcag taactttatc ccctgttgattccctagaat ctcctcacac gtatgtttcc 6480 gacaccacat cctctccaat gattacatcccctgggatct tacaggcctc acccaaccct 6540 atgttggcca ctgccgcccc tcctgccccagtccatgccc agcatgcact atctttttct 6600 aaccttcatg aaatgcagcc tttggcacatggggccagca ctgtgcttcc ctcagtgagc 6660 cagttgctat cccaccacca cattgtgtctccaggcagtg gcagtgctgg aagcttgagt 6720 aggctccatc cagtcccagt cccagcagattggatgaacc gcatggaggt gaatgagacc 6780 cagtacaatg agatgtttgg tatggtcctggctccagctg tagggcaccc atcctggcat 6840 agctccccag agaggccacc tgaagggaagcacataacca cccctcggga gcccttgccc 6900 cccattgtga ctttccagct catccctaaaggcagtattg cccaaccagc gggggctccc 6960 cagcctcagt ccacctgccc tccagctgttgcgggccccc tgcccaccat gtaccagatt 7020 ccagaaatgg cccgtttgcc cagtgtggctttccccactg ccatgatgcc ccagcaggac 7080 gggcaggtag ctcagaccat tctcccagcctatcatcctt tcccagcctc tgtgggcaag 7140 taccccacac ccccttcaca gcacagttatgcttcctcaa atgctgctga gcgaacaccc 7200 agtcacagtg gtcacctcca gggtgagcatccctacctga caccatcccc agagtctcct 7260 gaccagtggt caagttcatc accccactctgcttctgact ggtcagatgt gaccaccagc 7320 cctacccctg ggggagctgg aggaggtcagcggggacctg ggacacacat gtctgagcca 7380 ccacacaaca acatgcaggt ttatgcgtga7410 2 2469 PRT Homo sapiens 2 Met Pro Ala Leu Arg Pro Ala Leu Leu TrpAla Leu Leu Ala Leu Trp 1 5 10 15 Leu Cys Cys Ala Thr Pro Ala His AlaLeu Gln Cys Arg Asp Gly Tyr 20 25 30 Glu Pro Cys Val Asn Glu Gly Met CysVal Thr Tyr His Asn Gly Thr 35 40 45 Gly Tyr Cys Lys Cys Pro Glu Gly PheLeu Gly Glu Tyr Cys Gln His 50 55 60 Arg Asp Pro Cys Glu Lys Asn Arg CysGln Asn Gly Gly Thr Cys Val 65 70 75 80 Ala Gln Ala Met Leu Gly Lys AlaThr Cys Arg Cys Ala Ser Gly Phe 85 90 95 Thr Gly Glu Asp Cys Gln Tyr SerThr Ser His Pro Cys Phe Val Ser 100 105 110 Arg Pro Cys Leu Asn Gly GlyThr Cys His Met Leu Ser Arg Asp Thr 115 120 125 Tyr Glu Cys Thr Cys GlnVal Gly Phe Thr Gly Lys Glu Cys Gln Trp 130 135 140 Thr Asp Ala Cys LeuSer His Pro Cys Ala Asn Gly Ser Thr Cys Thr 145 150 155 160 Thr Val AlaAsn Gln Phe Ser Cys Lys Cys Leu Thr Gly Phe Thr Gly 165 170 175 Gln LysCys Glu Thr Asp Val Asn Glu Cys Asp Ile Pro Gly His Cys 180 185 190 GlnHis Gly Gly Thr Cys Leu Asn Leu Pro Gly Ser Tyr Gln Cys Gln 195 200 205Cys Pro Gln Gly Phe Thr Gly Gln Tyr Cys Asp Ser Leu Tyr Val Pro 210 215220 Cys Ala Pro Ser Pro Cys Val Asn Gly Gly Thr Cys Arg Gln Thr Gly 225230 235 240 Asp Phe Thr Phe Glu Cys His Leu Pro Gly Phe Glu Gly Ser ThrCys 245 250 255 Glu Arg Asn Ile Asp Asp Cys Pro Asn His Arg Cys Gln AsnGly Gly 260 265 270 Val Cys Val Asp Gly Val Asn Thr Tyr Asn Cys Arg CysPro Pro Gln 275 280 285 Trp Thr Gly Gln Phe Cys Thr Glu Asp Val Asp GluCys Leu Leu Gln 290 295 300 Pro Asn Ala Cys Gln Asn Trp Gly Thr Cys AlaAsn Arg Asn Gly Gly 305 310 315 320 Tyr Gly Cys Val Cys Val Asn Gly TrpSer Gly Asp Asp Cys Ser Glu 325 330 335 Asn Ile Asp Asp Cys Ala Phe GlyAla Cys Thr Pro Gly Ser Thr Cys 340 345 350 Ile Asp Arg Val Ala Ser PheSer Cys Met Cys Pro Glu Gly Lys Ala 355 360 365 Gly Leu Leu Cys His LeuAsp Asp Ala Cys Ile Ser Asn Pro Cys His 370 375 380 Lys Gly Ala Leu CysAsp Thr Asn Pro Leu Asn Gly Gln Tyr Ile Cys 385 390 395 400 Thr Cys ProGln Gly Tyr Lys Gly Ala Asp Cys Thr Glu Asp Val Asp 405 410 415 Glu CysAla Met Ala Asn Ser Asn Pro Cys Glu His Ala Gly Lys Cys 420 425 430 ValAsn Thr Asp Gly Ala Phe His Cys Glu Cys Leu Lys Gly Tyr Ala 435 440 445Gly Pro Arg Cys Glu Met Asp Ile Asn Glu Cys His Ser Asp Pro Cys 450 455460 Gln Asn Asp Ala Thr Cys Leu Asp Lys Ile Gly Gly Phe Thr Cys Leu 465470 475 480 Cys Met Pro Gly Phe Lys Gly Val His Cys Glu Leu Glu Ile AsnGlu 485 490 495 Cys Gln Ser Asn Pro Cys Val Asn Asn Gly Gln Cys Val AspLys Val 500 505 510 Asn Arg Phe Gln Cys Leu Cys Pro Pro Gly Phe Thr GlyPro Val Cys 515 520 525 Gln Ile Asp Ile Asp Asp Cys Ser Ser Thr Pro CysLeu Asn Gly Ala 530 535 540 Lys Cys Ile Asp His Pro Asn Gly Tyr Glu CysGln Cys Ala Thr Gly 545 550 555 560 Phe Thr Gly Val Leu Cys Glu Glu AsnIle Asp Asn Cys Asp Pro Asp 565 570 575 Pro Cys His His Gly Gln Cys GlnAsp Gly Ile Asp Ser Tyr Thr Cys 580 585 590 Ile Cys Asn Pro Gly Tyr MetGly Ala Ile Cys Ser Asp Gln Ile Asp 595 600 605 Glu Cys Tyr Ser Ser ProCys Leu Asn Asp Gly Arg Cys Ile Asp Leu 610 615 620 Val Asn Gly Tyr GlnCys Asn Cys Gln Pro Gly Thr Ser Gly Val Asn 625 630 635 640 Cys Glu IleAsn Phe Asp Asp Cys Ala Ser Asn Pro Cys Ile His Gly 645 650 655 Ile CysMet Asp Gly Ile Asn Arg Tyr Ser Cys Val Cys Ser Pro Gly 660 665 670 PheThr Gly Gln Arg Cys Asn Ile Asp Ile Asp Glu Cys Ala Ser Asn 675 680 685Pro Cys Arg Lys Gly Ala Thr Cys Ile Asn Gly Val Asn Gly Phe Arg 690 695700 Cys Ile Cys Pro Glu Gly Pro His His Pro Ser Cys Tyr Ser Gln Val 705710 715 720 Asn Glu Cys Leu Ser Asn Pro Cys Ile His Gly Asn Cys Thr GlyGly 725 730 735 Leu Ser Gly Tyr Lys Cys Leu Cys Asp Ala Gly Trp Val GlyIle Asn 740 745 750 Cys Glu Val Asp Lys Asn Glu Cys Leu Ser Asn Pro CysGln Asn Gly 755 760 765 Gly Thr Cys Asp Asn Leu Val Asn Gly Tyr Arg CysThr Cys Lys Lys 770 775 780 Gly Phe Lys Gly Tyr Asn Cys Gln Val Asn IleAsp Glu Cys Ala Ser 785 790 795 800 Asn Pro Cys Leu Asn Gln Gly Thr CysPhe Asp Asp Ile Ser Gly Tyr 805 810 815 Thr Cys His Cys Val Leu Pro TyrThr Gly Lys Asn Cys Gln Thr Val 820 825 830 Leu Ala Pro Cys Ser Pro AsnPro Cys Glu Asn Ala Ala Val Cys Lys 835 840 845 Glu Ser Pro Asn Phe GluSer Tyr Thr Cys Leu Cys Ala Pro Gly Trp 850 855 860 Gln Gly Gln Arg CysThr Ile Asp Ile Asp Glu Cys Ile Ser Lys Pro 865 870 875 880 Cys Met AsnHis Gly Leu Cys His Asn Thr Gln Gly Ser Tyr Met Cys 885 890 895 Glu CysPro Pro Gly Phe Ser Gly Met Asp Cys Glu Glu Asp Ile Asp 900 905 910 AspCys Leu Ala Ser Pro Cys Gln Asn Gly Gly Ser Cys Met Asp Gly 915 920 925Val Asn Thr Phe Ser Cys Leu Cys Leu Pro Gly Phe Thr Gly Asp Lys 930 935940 Cys Gln Thr Asp Met Asn Glu Cys Leu Ser Glu Pro Cys Lys Asn Gly 945950 955 960 Gly Thr Cys Ser Asp Tyr Val Asn Ser Tyr Thr Cys Lys Cys GlnAla 965 970 975 Gly Phe Asp Gly Val His Cys Glu Asn Asn Ile Asn Glu CysThr Glu 980 985 990 Ser Ser Cys Phe Asn Gly Gly Thr Cys Val Asp Gly IleAsn Ser Phe 995 1000 1005 Ser Cys Leu Cys Pro Val Gly Phe Thr Gly SerPhe Cys Leu His Glu 1010 1015 1020 Ile Asn Glu Cys Ser Ser His Pro CysLeu Asn Asp Gly Thr Cys Val 1025 1030 1035 1040 Asp Gly Leu Gly Thr TyrArg Cys Ser Cys Pro Leu Gly Tyr Thr Gly 1045 1050 1055 Lys Asn Cys GlnThr Leu Val Asn Leu Cys Ser Arg Ser Pro Cys Lys 1060 1065 1070 Asn LysGly Thr Cys Val Gln Lys Lys Ala Glu Ser Gln Cys Leu Cys 1075 1080 1085Pro Ser Gly Trp Ala Gly Ala Tyr Cys Asp Val Pro Asn Val Ser Cys 10901095 1100 Asp Ile Ala Ala Ser Arg Arg Gly Val Leu Val Glu His Leu CysGln 1105 1110 1115 1120 His Ser Gly Val Cys Ile Asn Ala Gly Asn Thr HisTyr Cys Gln Cys 1125 1130 1135 Pro Leu Gly Tyr Thr Gly Ser Tyr Cys GluGlu Gln Leu Asp Glu Cys 1140 1145 1150 Ala Ser Asn Pro Cys Gln His GlyAla Thr Cys Ser Asp Phe Ile Gly 1155 1160 1165 Gly Tyr Arg Cys Glu CysVal Pro Gly Tyr Gln Gly Val Asn Cys Glu 1170 1175 1180 Tyr Glu Val AspGlu Cys Gln Asn Gln Pro Cys Gln Asn Gly Gly Thr 1185 1190 1195 1200 CysIle Asp Leu Val Asn His Phe Lys Cys Ser Cys Pro Pro Gly Thr 1205 12101215 Arg Gly Met Lys Ser Ser Leu Ser Ile Phe His Cys Pro Gly Pro His1220 1225 1230 Cys Leu Asn Gly Gly Gln Cys Met Asp Arg Ile Gly Gly TyrSer Cys 1235 1240 1245 Arg Cys Leu Pro Gly Phe Ala Gly Glu Arg Cys GluGly Asp Ile Asn 1250 1255 1260 Glu Cys Leu Ser Asn Pro Cys Ser Ser GluGly Ser Leu Asp Cys Ile 1265 1270 1275 1280 Gln Leu Thr Asn Asp Tyr LeuCys Val Cys Arg Ser Ala Phe Thr Gly 1285 1290 1295 Arg His Cys Glu ThrPhe Val Asp Val Cys Pro Gln Met Pro Cys Leu 1300 1305 1310 Asn Gly GlyThr Cys Ala Val Ala Ser Asn Met Pro Asp Gly Ser Phe 1315 1320 1325 AlaVal Val Pro Gln Gly Phe Ser Gly Ala Arg Cys Gln Ser Ser Cys 1330 13351340 Gly Gln Val Lys Cys Arg Lys Gly Glu Gln Cys Val His Thr Ala Ser1345 1350 1355 1360 Gly Pro Arg Cys Phe Cys Pro Ser Pro Arg Asp Cys GluSer Gly Cys 1365 1370 1375 Ala Ser Ser Pro Cys Gln His Gly Gly Ser CysHis Pro Gln Arg Gln 1380 1385 1390 Pro Pro Tyr Tyr Ser Cys Gln Cys AlaPro Pro Phe Ser Gly Ser Arg 1395 1400 1405 Cys Glu Leu Tyr Thr Ala ProPro Ser Thr Pro Pro Ala Thr Cys Leu 1410 1415 1420 Ser Gln Tyr Cys AlaAsp Lys Ala Arg Asp Gly Val Cys Asp Glu Ala 1425 1430 1435 1440 Cys AsnSer His Ala Cys Gln Trp Asp Gly Gly Asp Cys Ser Leu Thr 1445 1450 1455Met Glu Asn Pro Trp Ala Asn Cys Ser Ser Pro Leu Pro Cys Trp Asp 14601465 1470 Tyr Ile Asn Asn Gln Cys Asp Glu Leu Cys Asn Thr Val Glu CysLeu 1475 1480 1485 Phe Asp Asn Phe Glu Cys Gln Gly Asn Ser Lys Thr CysLys Tyr Asp 1490 1495 1500 Lys Tyr Cys Ala Asp His Phe Lys Asp Asn HisCys Asp Gln Gly Cys 1505 1510 1515 1520 Asn Ser Glu Glu Cys Gly Trp AspGly Leu Asp Cys Ala Ala Asp Gln 1525 1530 1535 Pro Glu Asn Leu Ala GluGly Thr Leu Val Ile Val Val Leu Met Pro 1540 1545 1550 Pro Glu Gln LeuLeu Gln Asp Ala Arg Ser Phe Leu Arg Ala Leu Gly 1555 1560 1565 Thr LeuLeu His Thr Asn Leu Arg Ile Lys Arg Asp Ser Gln Gly Glu 1570 1575 1580Leu Met Val Tyr Pro Tyr Tyr Gly Glu Lys Ser Ala Ala Met Lys Lys 15851590 1595 1600 Gln Arg Met Thr Arg Arg Ser Leu Pro Gly Glu Gln Glu GlnGlu Val 1605 1610 1615 Ala Gly Ser Lys Val Phe Leu Glu Ile Asp Asn ArgGln Cys Val Gln 1620 1625 1630 Asp Ser Asp His Cys Phe Lys Asn Thr AspAla Ala Ala Ala Leu Leu 1635 1640 1645 Ala Ser His Ala Ile Gln Gly ThrLeu Ser Tyr Pro Leu Val Ser Val 1650 1655 1660 Val Ser Glu Ser Leu ThrPro Glu Arg Thr Gln Leu Leu Tyr Leu Leu 1665 1670 1675 1680 Ala Val AlaVal Val Ile Ile Leu Phe Ile Ile Leu Leu Gly Val Ile 1685 1690 1695 MetAla Lys Arg Lys Arg Lys His Gly Ser Leu Trp Leu Pro Glu Gly 1700 17051710 Phe Thr Leu Arg Arg Asp Ala Ser Asn His Lys Arg Arg Glu Pro Val1715 1720 1725 Gly Gln Asp Ala Val Gly Leu Lys Asn Leu Ser Val Gln ValSer Glu 1730 1735 1740 Ala Asn Leu Ile Gly Thr Gly Thr Ser Glu His TrpVal Asp Asp Glu 1745 1750 1755 1760 Gly Pro Gln Pro Lys Lys Val Lys AlaGlu Asp Glu Ala Leu Leu Ser 1765 1770 1775 Glu Glu Asp Asp Pro Ile AspArg Arg Pro Trp Thr Gln Gln His Leu 1780 1785 1790 Glu Ala Ala Asp IleArg Arg Thr Pro Ser Leu Ala Leu Thr Pro Pro 1795 1800 1805 Gln Ala GluGln Glu Val Asp Val Leu Asp Val Asn Val Arg Gly Pro 1810 1815 1820 AspGly Cys Thr Pro Leu Met Leu Ala Ser Leu Arg Gly Gly Ser Ser 1825 18301835 1840 Asp Leu Ser Asp Glu Asp Glu Asp Ala Glu Asp Ser Ser Ala AsnIle 1845 1850 1855 Ile Thr Asp Leu Val Tyr Gln Gly Ala Ser Leu Gln AlaGln Thr Asp 1860 1865 1870 Arg Thr Gly Glu Met Ala Leu His Leu Ala AlaArg Tyr Ser Arg Ala 1875 1880 1885 Asp Ala Ala Lys Arg Leu Leu Asp AlaGly Ala Asp Ala Asn Ala Gln 1890 1895 1900 Asp Asn Met Gly Arg Cys ProLeu His Ala Ala Val Ala Ala Asp Ala 1905 1910 1915 1920 Gln Gly Val PheGln Ile Leu Ile Arg Asn Arg Val Thr Asp Leu Asp 1925 1930 1935 Ala ArgMet Asn Asp Gly Thr Thr Pro Leu Ile Leu Ala Ala Arg Leu 1940 1945 1950Ala Val Glu Gly Met Val Ala Glu Leu Ile Asn Cys Gln Ala Asp Val 19551960 1965 Asn Ala Val Asp Asp His Gly Lys Ser Ala Leu His Trp Ala AlaAla 1970 1975 1980 Val Asn Asn Val Glu Ala Thr Leu Leu Leu Leu Lys AsnGly Ala Asn 1985 1990 1995 2000 Arg Asp Met Gln Asp Asn Lys Glu Glu ThrPro Leu Phe Leu Ala Ala 2005 2010 2015 Arg Glu Gly Ser Tyr Glu Ala AlaLys Ile Leu Leu Asp His Phe Ala 2020 2025 2030 Asn Arg Asp Ile Thr AspHis Met Asp Arg Leu Pro Arg Asp Val Ala 2035 2040 2045 Arg Asp Arg MetHis His Asp Ile Val Arg Leu Leu Asp Glu Tyr Asn 2050 2055 2060 Val ThrPro Ser Pro Pro Gly Thr Val Leu Thr Ser Ala Leu Ser Pro 2065 2070 20752080 Val Ile Cys Gly Pro Asn Arg Ser Phe Leu Ser Leu Lys His Thr Pro2085 2090 2095 Met Gly Lys Lys Ser Arg Arg Pro Ser Ala Lys Ser Thr MetPro Thr 2100 2105 2110 Ser Leu Pro Asn Leu Ala Lys Glu Ala Lys Asp AlaLys Gly Ser Arg 2115 2120 2125 Arg Lys Lys Ser Leu Ser Glu Lys Val GlnLeu Ser Glu Ser Ser Val 2130 2135 2140 Thr Leu Ser Pro Val Asp Ser LeuGlu Ser Pro His Thr Tyr Val Ser 2145 2150 2155 2160 Asp Thr Thr Ser SerPro Met Ile Thr Ser Pro Gly Ile Leu Gln Ala 2165 2170 2175 Ser Pro AsnPro Met Leu Ala Thr Ala Ala Pro Pro Ala Pro Val His 2180 2185 2190 AlaGln His Ala Leu Ser Phe Ser Asn Leu His Glu Met Gln Pro Leu 2195 22002205 Ala His Gly Ala Ser Thr Val Leu Pro Ser Val Ser Gln Leu Leu Ser2210 2215 2220 His His His Ile Val Ser Pro Gly Ser Gly Ser Ala Gly SerLeu Ser 2225 2230 2235 2240 Arg Leu His Pro Val Pro Val Pro Ala Asp TrpMet Asn Arg Met Glu 2245 2250 2255 Val Asn Glu Thr Gln Tyr Asn Glu MetPhe Gly Met Val Leu Ala Pro 2260 2265 2270 Ala Val Gly His Pro Ser TrpHis Ser Ser Pro Glu Arg Pro Pro Glu 2275 2280 2285 Gly Lys His Ile ThrThr Pro Arg Glu Pro Leu Pro Pro Ile Val Thr 2290 2295 2300 Phe Gln LeuIle Pro Lys Gly Ser Ile Ala Gln Pro Ala Gly Ala Pro 2305 2310 2315 2320Gln Pro Gln Ser Thr Cys Pro Pro Ala Val Ala Gly Pro Leu Pro Thr 23252330 2335 Met Tyr Gln Ile Pro Glu Met Ala Arg Leu Pro Ser Val Ala PhePro 2340 2345 2350 Thr Ala Met Met Pro Gln Gln Asp Gly Gln Val Ala GlnThr Ile Leu 2355 2360 2365 Pro Ala Tyr His Pro Phe Pro Ala Ser Val GlyLys Tyr Pro Thr Pro 2370 2375 2380 Pro Ser Gln His Ser Tyr Ala Ser SerAsn Ala Ala Glu Arg Thr Pro 2385 2390 2395 2400 Ser His Ser Gly His LeuGln Gly Glu His Pro Tyr Leu Thr Pro Ser 2405 2410 2415 Pro Glu Ser ProAsp Gln Trp Ser Ser Ser Ser Pro His Ser Ala Ser 2420 2425 2430 Asp TrpSer Asp Val Thr Thr Ser Pro Thr Pro Gly Gly Ala Gly Gly 2435 2440 2445Gly Gln Arg Gly Pro Gly Thr His Met Ser Glu Pro Pro His Asn Asn 24502455 2460 Met Gln Val Tyr Ala 2465 3 6728 DNA Homo sapiens 3 tcatctggaattatgcccgc cctgcgcccc gctctgctgt gggcgctgct ggcgctctgg 60 ctgtgctgcgcggcccccgc gcatgcattg cagtgtcgag atggctatga accctgtgta 120 aatgaaggaatgtgtgttac ctaccacaat ggcacaggat actgcaaatg tccagaaggc 180 ttcttgggggaatattgtca acatcgagac ccctgtgaga agaaccgctg ccagaatggt 240 gggacttgtgtggcccaggc catgctgggg aaagccacgt gccgatgtgc ctcagggttt 300 acaggagaggactgccagta ctcaacatct catccatgct ttgtgtctcg accctgcctg 360 aatggcggcacatgccatat gctcagccgg gatacctatg agtgcacctg tcaagtcggg 420 tttacaggtaaggagtgcca atggacggat gcctgcctgt ctcatccctg tgcaaatgga 480 agtacctgtaccactgtggc caaccagttc tcctgcaaat gcctcacagg cttcacaggg 540 cagaaatgtgagactgatgt caatgagtgt gacattccag gacactgcca gcatggtggc 600 acctgcctcaacctgcctgg ttcctaccag tgccagtgcc ctcagggctt cacaggccag 660 tactgtgacagcctgtatgt gccctgtgca ccctcacctt gtgtcaatgg aggcacctgt 720 cggcagactggtgacttcac ttttgagtgc aactgccttc caggttttga agggagcacc 780 tgtgagaggaatattgatga ctgccctaac cacaggtgtc agaatggagg ggtttgtgtg 840 gatggggtcaacacttacaa ctgccgctgt cccccacaat ggacaggaca gttctgcaca 900 gaggatgtggatgaatgcct gctgcagccc aatgcctgtc aaaatggggg cacctgtgcc 960 aaccgcaatggaggctatgg ctgtgtatgt gtcaacggct ggagtggaga tgactgcagt 1020 gagaacattgatgattgtgc cttcgcctcc tgtactccag gctccacctg catcgaccgt 1080 gtggcctccttctcttgcat gtgcccagag gggaaggcag gtctcctgtg tcatctggat 1140 gatgcatgcatcagcaatcc ttgccacaag ggggcactgt gtgacaccaa ccccctaaat 1200 gggcaatatatttgcacctg cccacaaggc tacaaagggg ctgactgcac agaagatgtg 1260 gatgaatgtgccatggccaa tagcaatcct tgtgagcatg caggaaaatg tgtgaacacg 1320 gatggcgccttccactgtga gtgtctgaag ggttatgcag gacctcgttg tgagatggac 1380 atcaatgagtgccattcaga cccctgccag aatgatgcta cctgtctgga taagattgga 1440 ggcttcacatgtctgtgcat gccaggtttc aaaggtgtgc attgtgaatt agaaataaat 1500 gaatgtcagagcaacccttg tgtgaacaat gggcagtgtg tggataaagt caatcgtttc 1560 cagtgcctgtgtcctcctgg tttcactggg ccagtttgcc agattgatat tgatgactgt 1620 tccagtactccgtgtctgaa tggggcaaag tgtatcgatc acccgaatgg ctatgaatgc 1680 cagtgtgccacaggtttcac tggtgtgttg tgtgaggaga acattgacaa ctgtgacccc 1740 gatccttgccaccatggtca gtgtcaggat ggtattgatt cctacacctg catctgcaat 1800 cccgggtacatgggcgccat ctgcagtgac cagattgatg aatgttacag cagcccttgc 1860 ctgaacgatggtcgctgcat tgacctggtc aatggctacc agtgcaactg ccagccaggc 1920 acgtcaggggttaattgtga aattaatttt gatgactgtg caagtaaccc ttgtatccat 1980 ggaatctgtatggatggcat taatcgctac agttgtgtct gctcaccagg attcacaggg 2040 cagagatgtaacattgacat tgatgagtgt gcctccaatc cctgtcgcaa gggtgcaaca 2100 tgtatcaacggtgtgaatgg tttccgctgt atatgccccg agggacccca tcaccccagc 2160 tgctactcacaggtgaacga atgcctgagc aatccctgca tccatggaaa ctgtactgga 2220 ggtctcagtggatataagtg tctctgtgat gcaggctggg ttggcatcaa ctgtgaagtg 2280 gacaaaaatgaatgcctttc gaatccatgc cagaatggag gaacttgtga caatctggtg 2340 aatggatacaggtgtacttg caagaagggc tttaaaggct ataactgcca ggtgaatatt 2400 gatgaatgtgcctcaaatcc atgcctgaac caaggaacct gctttgatga cataagtggc 2460 tacacttgccactgtgtgct gccatacaca ggcaagaatt gtcagacagt attggctccc 2520 tgttccccaaacccttgtga gaatgctgct gtttgcaaag agtcaccaaa ttttgagagt 2580 tatacttgcttgtgtgctcc tggctggcaa ggtcagcggt gtaccattga cattgacgag 2640 tgtatctccaagccctgcat gaaccatggt ctctgccata acacccaggg cagctacatg 2700 tgtgaatgtccaccaggctt cagtggtatg gactgtgagg aggacattga tgactgcctt 2760 gccaatccttgccagaatgg aggttcctgt atggatggag tgaatacttt ctcctgcctc 2820 tgccttccgggtttcactgg ggataagtgc cagacagaca tgaatgagtg tctgagtgaa 2880 ccctgtaagaatggagggac ctgctctgac tacgtcaaca gttacacttg caagtgccag 2940 gcaggatttgatggagtcca ttgtgagaac aacatcaatg agtgcactga gagctcctgt 3000 ttcaatggtggcacatgtgt tgatgggatt aactccttct cttgcttgtg ccctgtgggt 3060 ttcactggatccttctgcct ccatgagatc aatgaatgca gctctcatcc atgcctgaat 3120 gagggaacgtgtgttgatgg cctgggtacc taccgctgca gctgccccct gggctacact 3180 gggaaaaactgtcagaccct ggtgaatctc tgcagtcggt ctccatgtaa aaacaaaggt 3240 acttgtgttcagaaaaaagc agagtcccag tgcctatgtc catctggatg ggctggtgcc 3300 tattgtgacgtgcccaatgt ctcttgtgac atagcagcct ccaggagagg tgtgcttgtt 3360 gaacacttgtgccagcactc aggtgtctgc atcaatgctg gcaacacgca ttactgtcag 3420 tgccccctgggctatactgg gagctactgt gaggagcaac tcgatgagtg tgcgtccaac 3480 ccctgccagcacggggcaac atgcagtgac ttcattggtg gatacagatg cgagtgtgtc 3540 ccaggctatcagggtgtcaa ctgtgagtat gaagtggatg agtgccagaa tcagccctgc 3600 cagaatggaggcacctgtat tgaccttgtg aaccatttca agtgctcttg cccaccaggc 3660 actcggggcctactctgtga agagaacatt gatgactgtg cccggggtcc ccattgcctt 3720 aatggtggtcagtgcatgga taggattgga ggctacagtt gtcgctgctt gcctggcttt 3780 gctggggagcgttgtgaggg agacatcaac gagtgcctct ccaacccctg cagctctgag 3840 ggcagcctggactgtataca gctcaccaat gactacctgt gtgtttgccg tagtgccttt 3900 actggccggcactgtgaaac cttcgtcgat gtgtgtcccc agatgccctg cctgaatgga 3960 gggacttgtgctgtggccag taacatgcct gatggtttca tttgccgttg tcccccggga 4020 ttttccggggcaaggtacca gattccagaa atggcccgtt tgcccagtgt ggctttcccc 4080 actgccatgatgccccagca ggacgggcag gtagctcaga ccattctccc agcctatcat 4140 cctttcccagcctctgtggg caagtacccc acaccccctt cacagcacag ttatgcttcc 4200 tcaaatgctgctgagcgaac acccagtcac agtggtcacc tccagggtga gcatccctac 4260 ctgacaccatccccagagtc tcctgaccag tggtcaagtt catcacccca ctctgcttct 4320 gactggtcagatgtgaccac cagccctacc cctgggggtg ctggaggagg tcagcgggga 4380 cctgggacacacatgtctga gccaccacac aacaacatgc aggtttatgc gtgagagagt 4440 ccacctccagtgtagagaca taactgactt ttgtaaatgc tgctgaggaa caaatgaagg 4500 tcatccgggagagaaatgaa gaaatctctg gagccagctt ctagaggtag gaaagagaag 4560 atgttcttattcagataatg caagagaagc aattcgtcag tttcactggg tatctgcaag 4620 gcttattgattattctaatc taataagaca agtttgtgga aatgcaagat gaatacaagc 4680 cttgggtccatgtttactct cttctatttg gagaataaga tggatgctta ttgaagccca 4740 gacattcttgcagcttggac tgcattttaa gccctgcagg cttctgccat atccatgaga 4800 agattctacactagcgtcct gttgggaatt atgccctgga attctgcctg aattgaccta 4860 cgcatctcctcctccttgga cattcttttg tcttcatttg gtgcttttgg ttttgcacct 4920 ctccgtgattgtagccctac cagcatgtta tagggcaaga cctttgtgct tttgatcatt 4980 ctggcccatgaaagcaactt tggtctcctt tcccctcctg tcttcccggt atcccttgga 5040 gtctcacaaggtttactttg gtatggttct cagcacaaac ctttcaagta tgttgtttct 5100 ttggaaaatggacatactgt attgtgttct cctgcatata tcattcctgg agagagaagg 5160 ggagaagaatacttttcttc aacaaatttt gggggcagga gatcccttca agaggctgca 5220 ccttaatttttcttgtctgt gtgcaggtct tcatataaac tttaccagga agaagggtgt 5280 gagtttgttgtttttctgtg tatgggcctg gtcagtgtaa agttttatcc ttgatagtct 5340 agttactatgaccctcccca cttttttaaa accagaaaaa ggtttggaat gttggaatga 5400 ccaagagacaagttaactcg tgcaagagcc agttacccac ccacaggtcc ccctacttcc 5460 tgccaagcattccattgact gcctgtatgg aacacatttg tcccagatct gagcattcta 5520 ggcctgtttcactcactcac ccagcatatg aaactagtct taactgttga gcctttcctt 5580 tcatatccacagaagacact gtctcaaatg ttgtaccctt gccatttagg actgaacttt 5640 ccttagcccaagggacccag tgacagttgt cttccgtttg tcagatgatc agtctctact 5700 gattatcttgctgcttaaag gcctgctcac caatctttct ttcacaccgt gtggtccgtg 5760 ttactggtatacccagtatg ttctcactga agacatggac tttatatgtt caagtgcagg 5820 aattggaaagttggacttgt tttctatgat ccaaaacagc cctataagaa ggttggaaaa 5880 ggaggaactatatagcagcc tttgctattt tctgctacca tttcttttcc tctgaagcgg 5940 ccatgacattccctttggca actaacgtag aaactcaaca gaacattttc ctttcctaga 6000 gtcaccttttagatgataat ggacaactat agacttgctc attgttcaga ctgattgccc 6060 ctcacctgaatccactctct gtattcatgc tcttggcaat ttctttgact ttcttttaag 6120 ggcagaagcattttagttaa ttgtagataa agaatagttt tcttcctctt ctccttgggc 6180 cagttaataattggtccatg gctacactgc aacttccgtc cagtgctgtg atgcccatga 6240 cacctgcaaaataagttctg cctgggcatt ttgtagatat taacaggtga attcccgact 6300 cttttggtttgaatgacagt tctcattcct tctatggctg caagtatgca tcagtgcttc 6360 ccacttacctgatttgtctg tcggtggccc catatggaaa ccctgcgtgt ctgttggcat 6420 aatagtttacaaatggtttt ttcagtccta tccaaattta ttgaaccaac aaaaataatt 6480 acttctgccctgagataagc agattaagtt tgttcattct ctgctttatt ctctccatgt 6540 ggcaacattctgtcagcctc tttcatagtg tgcaaacatt ttatcattct aaatggtgac 6600 tctctgcccttggacccatt tattattcac agatggggag aacctatctg catggaccct 6660 caccatcctctgtgcagcac acacagtgca gggagccagt ggcgatggcg atgactttct 6720 tcccctgg6728 4 1473 PRT Homo sapiens 4 Met Pro Ala Leu Arg Pro Ala Leu Leu TrpAla Leu Leu Ala Leu Trp 1 5 10 15 Leu Cys Cys Ala Ala Pro Ala His AlaLeu Gln Cys Arg Asp Gly Tyr 20 25 30 Glu Pro Cys Val Asn Glu Gly Met CysVal Thr Tyr His Asn Gly Thr 35 40 45 Gly Tyr Cys Lys Cys Pro Glu Gly PheLeu Gly Glu Tyr Cys Gln His 50 55 60 Arg Asp Pro Cys Glu Lys Asn Arg CysGln Asn Gly Gly Thr Cys Val 65 70 75 80 Ala Gln Ala Met Leu Gly Lys AlaThr Cys Arg Cys Ala Ser Gly Phe 85 90 95 Thr Gly Glu Asp Cys Gln Tyr SerThr Ser His Pro Cys Phe Val Ser 100 105 110 Arg Pro Cys Leu Asn Gly GlyThr Cys His Met Leu Ser Arg Asp Thr 115 120 125 Tyr Glu Cys Thr Cys GlnVal Gly Phe Thr Gly Lys Glu Cys Gln Trp 130 135 140 Thr Asp Ala Cys LeuSer His Pro Cys Ala Asn Gly Ser Thr Cys Thr 145 150 155 160 Thr Val AlaAsn Gln Phe Ser Cys Lys Cys Leu Thr Gly Phe Thr Gly 165 170 175 Gln LysCys Glu Thr Asp Val Asn Glu Cys Asp Ile Pro Gly His Cys 180 185 190 GlnHis Gly Gly Thr Cys Leu Asn Leu Pro Gly Ser Tyr Gln Cys Gln 195 200 205Cys Pro Gln Gly Phe Thr Gly Gln Tyr Cys Asp Ser Leu Tyr Val Pro 210 215220 Cys Ala Pro Ser Pro Cys Val Asn Gly Gly Thr Cys Arg Gln Thr Gly 225230 235 240 Asp Phe Thr Phe Glu Cys Asn Cys Leu Pro Gly Phe Glu Gly SerThr 245 250 255 Cys Glu Arg Asn Ile Asp Asp Cys Pro Asn His Arg Cys GlnAsn Gly 260 265 270 Gly Val Cys Val Asp Gly Val Asn Thr Tyr Asn Cys ArgCys Pro Pro 275 280 285 Gln Trp Thr Gly Gln Phe Cys Thr Glu Asp Val AspGlu Cys Leu Leu 290 295 300 Gln Pro Asn Ala Cys Gln Asn Gly Gly Thr CysAla Asn Arg Asn Gly 305 310 315 320 Gly Tyr Gly Cys Val Cys Val Asn GlyTrp Ser Gly Asp Asp Cys Ser 325 330 335 Glu Asn Ile Asp Asp Cys Ala PheAla Ser Cys Thr Pro Gly Ser Thr 340 345 350 Cys Ile Asp Arg Val Ala SerPhe Ser Cys Met Cys Pro Glu Gly Lys 355 360 365 Ala Gly Leu Leu Cys HisLeu Asp Asp Ala Cys Ile Ser Asn Pro Cys 370 375 380 His Lys Gly Ala LeuCys Asp Thr Asn Pro Leu Asn Gly Gln Tyr Ile 385 390 395 400 Cys Thr CysPro Gln Gly Tyr Lys Gly Ala Asp Cys Thr Glu Asp Val 405 410 415 Asp GluCys Ala Met Ala Asn Ser Asn Pro Cys Glu His Ala Gly Lys 420 425 430 CysVal Asn Thr Asp Gly Ala Phe His Cys Glu Cys Leu Lys Gly Tyr 435 440 445Ala Gly Pro Arg Cys Glu Met Asp Ile Asn Glu Cys His Ser Asp Pro 450 455460 Cys Gln Asn Asp Ala Thr Cys Leu Asp Lys Ile Gly Gly Phe Thr Cys 465470 475 480 Leu Cys Met Pro Gly Phe Lys Gly Val His Cys Glu Leu Glu IleAsn 485 490 495 Glu Cys Gln Ser Asn Pro Cys Val Asn Asn Gly Gln Cys ValAsp Lys 500 505 510 Val Asn Arg Phe Gln Cys Leu Cys Pro Pro Gly Phe ThrGly Pro Val 515 520 525 Cys Gln Ile Asp Ile Asp Asp Cys Ser Ser Thr ProCys Leu Asn Gly 530 535 540 Ala Lys Cys Ile Asp His Pro Asn Gly Tyr GluCys Gln Cys Ala Thr 545 550 555 560 Gly Phe Thr Gly Val Leu Cys Glu GluAsn Ile Asp Asn Cys Asp Pro 565 570 575 Asp Pro Cys His His Gly Gln CysGln Asp Gly Ile Asp Ser Tyr Thr 580 585 590 Cys Ile Cys Asn Pro Gly TyrMet Gly Ala Ile Cys Ser Asp Gln Ile 595 600 605 Asp Glu Cys Tyr Ser SerPro Cys Leu Asn Asp Gly Arg Cys Ile Asp 610 615 620 Leu Val Asn Gly TyrGln Cys Asn Cys Gln Pro Gly Thr Ser Gly Val 625 630 635 640 Asn Cys GluIle Asn Phe Asp Asp Cys Ala Ser Asn Pro Cys Ile His 645 650 655 Gly IleCys Met Asp Gly Ile Asn Arg Tyr Ser Cys Val Cys Ser Pro 660 665 670 GlyPhe Thr Gly Gln Arg Cys Asn Ile Asp Ile Asp Glu Cys Ala Ser 675 680 685Asn Pro Cys Arg Lys Gly Ala Thr Cys Ile Asn Gly Val Asn Gly Phe 690 695700 Arg Cys Ile Cys Pro Glu Gly Pro His His Pro Ser Cys Tyr Ser Gln 705710 715 720 Val Asn Glu Cys Leu Ser Asn Pro Cys Ile His Gly Asn Cys ThrGly 725 730 735 Gly Leu Ser Gly Tyr Lys Cys Leu Cys Asp Ala Gly Trp ValGly Ile 740 745 750 Asn Cys Glu Val Asp Lys Asn Glu Cys Leu Ser Asn ProCys Gln Asn 755 760 765 Gly Gly Thr Cys Asp Asn Leu Val Asn Gly Tyr ArgCys Thr Cys Lys 770 775 780 Lys Gly Phe Lys Gly Tyr Asn Cys Gln Val AsnIle Asp Glu Cys Ala 785 790 795 800 Ser Asn Pro Cys Leu Asn Gln Gly ThrCys Phe Asp Asp Ile Ser Gly 805 810 815 Tyr Thr Cys His Cys Val Leu ProTyr Thr Gly Lys Asn Cys Gln Thr 820 825 830 Val Leu Ala Pro Cys Ser ProAsn Pro Cys Glu Asn Ala Ala Val Cys 835 840 845 Lys Glu Ser Pro Asn PheGlu Ser Tyr Thr Cys Leu Cys Ala Pro Gly 850 855 860 Trp Gln Gly Gln ArgCys Thr Ile Asp Ile Asp Glu Cys Ile Ser Lys 865 870 875 880 Pro Cys MetAsn His Gly Leu Cys His Asn Thr Gln Gly Ser Tyr Met 885 890 895 Cys GluCys Pro Pro Gly Phe Ser Gly Met Asp Cys Glu Glu Asp Ile 900 905 910 AspAsp Cys Leu Ala Asn Pro Cys Gln Asn Gly Gly Ser Cys Met Asp 915 920 925Gly Val Asn Thr Phe Ser Cys Leu Cys Leu Pro Gly Phe Thr Gly Asp 930 935940 Lys Cys Gln Thr Asp Met Asn Glu Cys Leu Ser Glu Pro Cys Lys Asn 945950 955 960 Gly Gly Thr Cys Ser Asp Tyr Val Asn Ser Tyr Thr Cys Lys CysGln 965 970 975 Ala Gly Phe Asp Gly Val His Cys Glu Asn Asn Ile Asn GluCys Thr 980 985 990 Glu Ser Ser Cys Phe Asn Gly Gly Thr Cys Val Asp GlyIle Asn Ser 995 1000 1005 Phe Ser Cys Leu Cys Pro Val Gly Phe Thr GlySer Phe Cys Leu His 1010 1015 1020 Glu Ile Asn Glu Cys Ser Ser His ProCys Leu Asn Glu Gly Thr Cys 1025 1030 1035 1040 Val Asp Gly Leu Gly ThrTyr Arg Cys Ser Cys Pro Leu Gly Tyr Thr 1045 1050 1055 Gly Lys Asn CysGln Thr Leu Val Asn Leu Cys Ser Arg Ser Pro Cys 1060 1065 1070 Lys AsnLys Gly Thr Cys Val Gln Lys Lys Ala Glu Ser Gln Cys Leu 1075 1080 1085Cys Pro Ser Gly Trp Ala Gly Ala Tyr Cys Asp Val Pro Asn Val Ser 10901095 1100 Cys Asp Ile Ala Ala Ser Arg Arg Gly Val Leu Val Glu His LeuCys 1105 1110 1115 1120 Gln His Ser Gly Val Cys Ile Asn Ala Gly Asn ThrHis Tyr Cys Gln 1125 1130 1135 Cys Pro Leu Gly Tyr Thr Gly Ser Tyr CysGlu Glu Gln Leu Asp Glu 1140 1145 1150 Cys Ala Ser Asn Pro Cys Gln HisGly Ala Thr Cys Ser Asp Phe Ile 1155 1160 1165 Gly Gly Tyr Arg Cys GluCys Val Pro Gly Tyr Gln Gly Val Asn Cys 1170 1175 1180 Glu Tyr Glu ValAsp Glu Cys Gln Asn Gln Pro Cys Gln Asn Gly Gly 1185 1190 1195 1200 ThrCys Ile Asp Leu Val Asn His Phe Lys Cys Ser Cys Pro Pro Gly 1205 12101215 Thr Arg Gly Leu Leu Cys Glu Glu Asn Ile Asp Asp Cys Ala Arg Gly1220 1225 1230 Pro His Cys Leu Asn Gly Gly Gln Cys Met Asp Arg Ile GlyGly Tyr 1235 1240 1245 Ser Cys Arg Cys Leu Pro Gly Phe Ala Gly Glu ArgCys Glu Gly Asp 1250 1255 1260 Ile Asn Glu Cys Leu Ser Asn Pro Cys SerSer Glu Gly Ser Leu Asp 1265 1270 1275 1280 Cys Ile Gln Leu Thr Asn AspTyr Leu Cys Val Cys Arg Ser Ala Phe 1285 1290 1295 Thr Gly Arg His CysGlu Thr Phe Val Asp Val Cys Pro Gln Met Pro 1300 1305 1310 Cys Leu AsnGly Gly Thr Cys Ala Val Ala Ser Asn Met Pro Asp Gly 1315 1320 1325 PheIle Cys Arg Cys Pro Pro Gly Phe Ser Gly Ala Arg Tyr Gln Ile 1330 13351340 Pro Glu Met Ala Arg Leu Pro Ser Val Ala Phe Pro Thr Ala Met Met1345 1350 1355 1360 Pro Gln Gln Asp Gly Gln Val Ala Gln Thr Ile Leu ProAla Tyr His 1365 1370 1375 Pro Phe Pro Ala Ser Val Gly Lys Tyr Pro ThrPro Pro Ser Gln His 1380 1385 1390 Ser Tyr Ala Ser Ser Asn Ala Ala GluArg Thr Pro Ser His Ser Gly 1395 1400 1405 His Leu Gln Gly Glu His ProTyr Leu Thr Pro Ser Pro Glu Ser Pro 1410 1415 1420 Asp Gln Trp Ser SerSer Ser Pro His Ser Ala Ser Asp Trp Ser Asp 1425 1430 1435 1440 Val ThrThr Ser Pro Thr Pro Gly Gly Ala Gly Gly Gly Gln Arg Gly 1445 1450 1455Pro Gly Thr His Met Ser Glu Pro Pro His Asn Asn Met Gln Val Tyr 14601465 1470 Ala 5 2631 DNA Homo sapiens 5 atgatttaca tacaagtaat ttttcaagtaatgaccattg aaaaaatgtt ttctttttat 60 tttttagatt atttctcttt attcagaagcatacagttgt ttgctgattg caagaagatg 120 tttctgtggc tgtttctgat tttgtcagccctgatttctt cgacaaatgc agattctgac 180 atatcggtgg aaatttgcaa tgtgtgttcctgcgtgtcag ttgagaatgt gctctatgtc 240 aactgtgaga aggtttcagt ctacagaccaaatcagctga aaccaccttg gtctaatttt 300 tatcacctca atttccaaaa taattttttaaatattctgt atccaaatac attcttgaat 360 ttttcacatg cagtctccct gcatctggggaataataaac tgcagaacat tgagggagga 420 gcctttcttg ggctcagtgc attaaagcagttgcacttga acaacaatga attaaagatt 480 ctccgagctg acactttcct tggcatagagaacttggagt atctccaggc tgactacaat 540 ttaatcaagt atattgaacg aggagccttcaataagctcc acaaactgaa agttctcatt 600 cttaatgaca atctgatttc attccttcctgataatattt tccgattcgc atctttgacc 660 catctggata tacgagggaa cagaatccagaagctccctt atatcggggt tctggaacac 720 attggccgtg tcgttgaatt gcaactggaagataaccctt ggaactgtag ctgtgattta 780 ttgcccttaa aagcttggct ggagaacatgccatataaca tttacatagg agaagctatc 840 tgtgaaactc ccagtgactt atatggaaggcttttaaaag aaaccaacaa acaagagcta 900 tgtcccatgg gcaccggcag tgattttgacgtgcgcatcc tgcctccatc tcagctggaa 960 aatggctaca ccactcccaa tggtcacactacccaaacat ctttacacag attagtaact 1020 aaaccaccaa aaacaacaaa tccttccaagatctctggaa tcgttgcagg caaagccctc 1080 tccaaccgca atctcagtca gattgtgtcttaccaaacaa gggtgcctcc tctaacacct 1140 tgcccggcac cttgcttctg caaaacacacccttcagatt tgggactaag tgtgaactgc 1200 caagagaaaa atatacagtc tatgtctgaactgataccga aacctttaaa tgcgaagaag 1260 ctgcacgtca atggcaatag catcaaggatgtggacgtat cagacttcac tgactttgaa 1320 ggactggatt tgcttcatct aggcagcaatcaaattacag tgattaaggg agacgtattt 1380 cacaatctca ctaatttacg caggctatatctcaatggca atcaaattga gagactctat 1440 cctgaaatat tttcaggtct tcataacctgcagtatctgt atttggaata caatttgatt 1500 aaggaaatct cagcaggcac ctttgactccatgccaaatt tgcagttact gtacttaaac 1560 aataatctcc taaagagcct gcctgtttacatcttttccg gagcaccctt agctagactg 1620 aacctgagga acaacaaatt catgtacctgcctgtcagtg gggtccttga tcagttgcaa 1680 tctcttacac agattgactt ggagggcaacccatgggact gtacttgtga cttggtggca 1740 ttaaagctgt gggtggagaa gttgagcgacgggattgttg tgaaagaact gaaatgtgag 1800 acgcctgttc agtttgccaa cattgaactgaagtccctca aaaatgaaat cttatgtccc 1860 aaacttttaa ataagccgtc tgcaccattcacaagccctg cacctgccat tacattcacc 1920 actcctttgg gtcccattcg aagtcctcctggtgggccag tgcctctgtc tattttaatc 1980 ttaagtatct tagtggtcct cattttaacggtgtttgttg ctttttgcct tcttgttttt 2040 gtcctgcgac gcaacaagaa acccacagtgaagcacgaag gcctggggaa tcctgactgt 2100 ggctccatgc agctgcagct aaggaagcatgaccacaaaa ccaataaaaa agatggactg 2160 agcacagaag ctttcattcc acaaactatagaacagatga gcaagagcca cacttgtggc 2220 ttgaaagagt cagaaactgg gttcatgttttcagatcctc caggacagaa agttgttatg 2280 agaaatgtgg ccgacaagga gaaagatttattacatgtag ataccaggaa gagactgagc 2340 acaattgatg agctggatga attattccctagcagggatt ccaatgtgtt tattcagaat 2400 tttcttgaaa gcaaaaagga gtataatagcataggtgtca gtggctttga gatccgctat 2460 ccagaaaaac aaccagacaa aaaaagtaagaagtcactga taggtggcaa ccacagtaaa 2520 attgttgtgg aacaaaggaa gagtgagtattttgaactga aggcgaaact gcagagttcc 2580 cctgactacc tacaggtcct tgaggagcaaacagctttga acaagatcta g 2631 6 876 PRT Homo sapiens 6 Met Ile Tyr IleGln Val Ile Phe Gln Val Met Thr Ile Glu Lys Met 1 5 10 15 Phe Ser PheTyr Phe Leu Asp Tyr Phe Ser Leu Phe Arg Ser Ile Gln 20 25 30 Leu Phe AlaAsp Cys Lys Lys Met Phe Leu Trp Leu Phe Leu Ile Leu 35 40 45 Ser Ala LeuIle Ser Ser Thr Asn Ala Asp Ser Asp Ile Ser Val Glu 50 55 60 Ile Cys AsnVal Cys Ser Cys Val Ser Val Glu Asn Val Leu Tyr Val 65 70 75 80 Asn CysGlu Lys Val Ser Val Tyr Arg Pro Asn Gln Leu Lys Pro Pro 85 90 95 Trp SerAsn Phe Tyr His Leu Asn Phe Gln Asn Asn Phe Leu Asn Ile 100 105 110 LeuTyr Pro Asn Thr Phe Leu Asn Phe Ser His Ala Val Ser Leu His 115 120 125Leu Gly Asn Asn Lys Leu Gln Asn Ile Glu Gly Gly Ala Phe Leu Gly 130 135140 Leu Ser Ala Leu Lys Gln Leu His Leu Asn Asn Asn Glu Leu Lys Ile 145150 155 160 Leu Arg Ala Asp Thr Phe Leu Gly Ile Glu Asn Leu Glu Tyr LeuGln 165 170 175 Ala Asp Tyr Asn Leu Ile Lys Tyr Ile Glu Arg Gly Ala PheAsn Lys 180 185 190 Leu His Lys Leu Lys Val Leu Ile Leu Asn Asp Asn LeuIle Ser Phe 195 200 205 Leu Pro Asp Asn Ile Phe Arg Phe Ala Ser Leu ThrHis Leu Asp Ile 210 215 220 Arg Gly Asn Arg Ile Gln Lys Leu Pro Tyr IleGly Val Leu Glu His 225 230 235 240 Ile Gly Arg Val Val Glu Leu Gln LeuGlu Asp Asn Pro Trp Asn Cys 245 250 255 Ser Cys Asp Leu Leu Pro Leu LysAla Trp Leu Glu Asn Met Pro Tyr 260 265 270 Asn Ile Tyr Ile Gly Glu AlaIle Cys Glu Thr Pro Ser Asp Leu Tyr 275 280 285 Gly Arg Leu Leu Lys GluThr Asn Lys Gln Glu Leu Cys Pro Met Gly 290 295 300 Thr Gly Ser Asp PheAsp Val Arg Ile Leu Pro Pro Ser Gln Leu Glu 305 310 315 320 Asn Gly TyrThr Thr Pro Asn Gly His Thr Thr Gln Thr Ser Leu His 325 330 335 Arg LeuVal Thr Lys Pro Pro Lys Thr Thr Asn Pro Ser Lys Ile Ser 340 345 350 GlyIle Val Ala Gly Lys Ala Leu Ser Asn Arg Asn Leu Ser Gln Ile 355 360 365Val Ser Tyr Gln Thr Arg Val Pro Pro Leu Thr Pro Cys Pro Ala Pro 370 375380 Cys Phe Cys Lys Thr His Pro Ser Asp Leu Gly Leu Ser Val Asn Cys 385390 395 400 Gln Glu Lys Asn Ile Gln Ser Met Ser Glu Leu Ile Pro Lys ProLeu 405 410 415 Asn Ala Lys Lys Leu His Val Asn Gly Asn Ser Ile Lys AspVal Asp 420 425 430 Val Ser Asp Phe Thr Asp Phe Glu Gly Leu Asp Leu LeuHis Leu Gly 435 440 445 Ser Asn Gln Ile Thr Val Ile Lys Gly Asp Val PheHis Asn Leu Thr 450 455 460 Asn Leu Arg Arg Leu Tyr Leu Asn Gly Asn GlnIle Glu Arg Leu Tyr 465 470 475 480 Pro Glu Ile Phe Ser Gly Leu His AsnLeu Gln Tyr Leu Tyr Leu Glu 485 490 495 Tyr Asn Leu Ile Lys Glu Ile SerAla Gly Thr Phe Asp Ser Met Pro 500 505 510 Asn Leu Gln Leu Leu Tyr LeuAsn Asn Asn Leu Leu Lys Ser Leu Pro 515 520 525 Val Tyr Ile Phe Ser GlyAla Pro Leu Ala Arg Leu Asn Leu Arg Asn 530 535 540 Asn Lys Phe Met TyrLeu Pro Val Ser Gly Val Leu Asp Gln Leu Gln 545 550 555 560 Ser Leu ThrGln Ile Asp Leu Glu Gly Asn Pro Trp Asp Cys Thr Cys 565 570 575 Asp LeuVal Ala Leu Lys Leu Trp Val Glu Lys Leu Ser Asp Gly Ile 580 585 590 ValVal Lys Glu Leu Lys Cys Glu Thr Pro Val Gln Phe Ala Asn Ile 595 600 605Glu Leu Lys Ser Leu Lys Asn Glu Ile Leu Cys Pro Lys Leu Leu Asn 610 615620 Lys Pro Ser Ala Pro Phe Thr Ser Pro Ala Pro Ala Ile Thr Phe Thr 625630 635 640 Thr Pro Leu Gly Pro Ile Arg Ser Pro Pro Gly Gly Pro Val ProLeu 645 650 655 Ser Ile Leu Ile Leu Ser Ile Leu Val Val Leu Ile Leu ThrVal Phe 660 665 670 Val Ala Phe Cys Leu Leu Val Phe Val Leu Arg Arg AsnLys Lys Pro 675 680 685 Thr Val Lys His Glu Gly Leu Gly Asn Pro Asp CysGly Ser Met Gln 690 695 700 Leu Gln Leu Arg Lys His Asp His Lys Thr AsnLys Lys Asp Gly Leu 705 710 715 720 Ser Thr Glu Ala Phe Ile Pro Gln ThrIle Glu Gln Met Ser Lys Ser 725 730 735 His Thr Cys Gly Leu Lys Glu SerGlu Thr Gly Phe Met Phe Ser Asp 740 745 750 Pro Pro Gly Gln Lys Val ValMet Arg Asn Val Ala Asp Lys Glu Lys 755 760 765 Asp Leu Leu His Val AspThr Arg Lys Arg Leu Ser Thr Ile Asp Glu 770 775 780 Leu Asp Glu Leu PhePro Ser Arg Asp Ser Asn Val Phe Ile Gln Asn 785 790 795 800 Phe Leu GluSer Lys Lys Glu Tyr Asn Ser Ile Gly Val Ser Gly Phe 805 810 815 Glu IleArg Tyr Pro Glu Lys Gln Pro Asp Lys Lys Ser Lys Lys Ser 820 825 830 LeuIle Gly Gly Asn His Ser Lys Ile Val Val Glu Gln Arg Lys Ser 835 840 845Glu Tyr Phe Glu Leu Lys Ala Lys Leu Gln Ser Ser Pro Asp Tyr Leu 850 855860 Gln Val Leu Glu Glu Gln Thr Ala Leu Asn Lys Ile 865 870 875 7 2271DNA Homo sapiens 7 atggccctcc cagccctggg cctggacccc tggagcctcctgggcctttt cctcttccaa 60 ctgcttcagc tgctgctgcc gacgacgacc gcggggggaggcgggcaggg gcccatgccc 120 agggtcagat actatgcagg ggatgaacgt agggcacttagcttcttcca ccagaagggc 180 ctccaggatt ttgacactct gctcctgagt ggtgatggaaatactctcta cgtgggggct 240 cgagaagcca ttctggcctt ggatatccag gatccaggggtccccaggct aaagaacatg 300 ataccgtggc cagccagtga cagaaaaaag agtgaatgtgcctttaagaa gaagagcaat 360 gagacacagt gtttcaactt catccgtgtc ctggtttcttacaatgtcac ccatctctac 420 acctgcggca ccttcgcctt cagccctgct tgtaccttcattgaacttca agattcctac 480 ctgttgccca tctcggagga caaggtcatg gagggaaaaggccaaagccc ctttgacccc 540 gctcacaagc atacggctgt cttggtggat gggatgctctattctggtac tatgaacaac 600 ttcctgggca gtgagcccat cctgatgcgc acactgggatcccagcctgt cctcaagacc 660 gacaacttcc tccgctggct gcatcatgac gcctcctttgtggcagccat cccttcgacc 720 caggtcgtct acttcttctt cgaggagaca gccagcgagtttgacttctt tgagaggctc 780 cacacatcgc gggtggctag agtctgcaag aatgacgtgggcggcgaaaa gctgctgcag 840 aagaagtgga ccaccttcct gaaggcccag ctgctctgcacccagccggg gcagctgccc 900 ttcaacgtca tccgccacgc ggtcctgctc cccgccgattctcccacagc tccccacatc 960 tacgcagtct tcacctccca gtggcaggtt ggcgggaccaggagctctgc ggtttgtgcc 1020 ttctctctct tggacattga acgtgtcttt aaggggaaatacaaagagtt gaacaaagaa 1080 acttcacgct ggactactta taggggccct gagaccaacccccggccagg cagttgctca 1140 gtgggcccct cctctgataa ggccctgacc ttcatgaaggaccatttcct gatggatgag 1200 caagtggtgg ggacgcccct gctggtgaaa tctggcgtggagtatacacg gcttgcagtg 1260 gagacagccc agggccttga tgggcacagc catcttgtcatgtacctggg aaccagtaca 1320 gggtcgctcc acaaggctgt ggtaagtggg gacagcagtgctcatctggt ggaagagatt 1380 cagctgttcc ctgaccctga acctgttcgc aacctgcagctggcccccac ccagggtgca 1440 gtgtttgtag gcttctcagg aggtgtctgg agggtgccccgagccaactg tagtgtctat 1500 gagagctgtg tggactgtgt ccttgcccgg gacccccactgtgcctggga ccctgagtcc 1560 cgactctgct ctcttaggaa ctcctggaag caggacatggagcgggggaa cccagagtgg 1620 gcatgtgcca gtggccccat gagcaggagc cttcggcctcagagccgccc gcaaatcgtt 1680 aaagaagtcc tggctgtccc caactccatc ctggagctcccctgccccca cctgtcagcc 1740 ttggcctctt attattggag tcatggccca gcagcagtcccagaagcctc ttccactgtc 1800 tacaatggct ccctcttgct gatagtgcag gatggagttgggggtctcta ccagtgctgg 1860 gcaactgaga atggcttttc ataccctgtg atctcctactgggtggacag ccaggaccag 1920 accctggccc tggatcctga actggcaggc atcccccgggagcatgtgaa ggtcccgttg 1980 accagggtca gtggtggggc cgccctggct gcccagcagtcctactggcc ccactttgtc 2040 actgtcactg tcctctttgc cttagtgctt tcaggagccctcatcatcct cgtggcctcc 2100 ccattgagag cactccgggc tcggggcaag gttcagggctgtgagaccct gcgccctggg 2160 gagaaggccc cgttaagcag agagcaacac ctccagtctcccaaggaatg caggacctct 2220 gccagtgatg tggacgctga caacaactgc ctaggcactgaggtagctta a 2271 8 756 PRT Homo sapiens 8 Met Ala Leu Pro Ala Leu GlyLeu Asp Pro Trp Ser Leu Leu Gly Leu 1 5 10 15 Phe Leu Phe Gln Leu LeuGln Leu Leu Leu Pro Thr Thr Thr Ala Gly 20 25 30 Gly Gly Gly Gln Gly ProMet Pro Arg Val Arg Tyr Tyr Ala Gly Asp 35 40 45 Glu Arg Arg Ala Leu SerPhe Phe His Gln Lys Gly Leu Gln Asp Phe 50 55 60 Asp Thr Leu Leu Leu SerGly Asp Gly Asn Thr Leu Tyr Val Gly Ala 65 70 75 80 Arg Glu Ala Ile LeuAla Leu Asp Ile Gln Asp Pro Gly Val Pro Arg 85 90 95 Leu Lys Asn Met IlePro Trp Pro Ala Ser Asp Arg Lys Lys Ser Glu 100 105 110 Cys Ala Phe LysLys Lys Ser Asn Glu Thr Gln Cys Phe Asn Phe Ile 115 120 125 Arg Val LeuVal Ser Tyr Asn Val Thr His Leu Tyr Thr Cys Gly Thr 130 135 140 Phe AlaPhe Ser Pro Ala Cys Thr Phe Ile Glu Leu Gln Asp Ser Tyr 145 150 155 160Leu Leu Pro Ile Ser Glu Asp Lys Val Met Glu Gly Lys Gly Gln Ser 165 170175 Pro Phe Asp Pro Ala His Lys His Thr Ala Val Leu Val Asp Gly Met 180185 190 Leu Tyr Ser Gly Thr Met Asn Asn Phe Leu Gly Ser Glu Pro Ile Leu195 200 205 Met Arg Thr Leu Gly Ser Gln Pro Val Leu Lys Thr Asp Asn PheLeu 210 215 220 Arg Trp Leu His His Asp Ala Ser Phe Val Ala Ala Ile ProSer Thr 225 230 235 240 Gln Val Val Tyr Phe Phe Phe Glu Glu Thr Ala SerGlu Phe Asp Phe 245 250 255 Phe Glu Arg Leu His Thr Ser Arg Val Ala ArgVal Cys Lys Asn Asp 260 265 270 Val Gly Gly Glu Lys Leu Leu Gln Lys LysTrp Thr Thr Phe Leu Lys 275 280 285 Ala Gln Leu Leu Cys Thr Gln Pro GlyGln Leu Pro Phe Asn Val Ile 290 295 300 Arg His Ala Val Leu Leu Pro AlaAsp Ser Pro Thr Ala Pro His Ile 305 310 315 320 Tyr Ala Val Phe Thr SerGln Trp Gln Val Gly Gly Thr Arg Ser Ser 325 330 335 Ala Val Cys Ala PheSer Leu Leu Asp Ile Glu Arg Val Phe Lys Gly 340 345 350 Lys Tyr Lys GluLeu Asn Lys Glu Thr Ser Arg Trp Thr Thr Tyr Arg 355 360 365 Gly Pro GluThr Asn Pro Arg Pro Gly Ser Cys Ser Val Gly Pro Ser 370 375 380 Ser AspLys Ala Leu Thr Phe Met Lys Asp His Phe Leu Met Asp Glu 385 390 395 400Gln Val Val Gly Thr Pro Leu Leu Val Lys Ser Gly Val Glu Tyr Thr 405 410415 Arg Leu Ala Val Glu Thr Ala Gln Gly Leu Asp Gly His Ser His Leu 420425 430 Val Met Tyr Leu Gly Thr Ser Thr Gly Ser Leu His Lys Ala Val Val435 440 445 Ser Gly Asp Ser Ser Ala His Leu Val Glu Glu Ile Gln Leu PhePro 450 455 460 Asp Pro Glu Pro Val Arg Asn Leu Gln Leu Ala Pro Thr GlnGly Ala 465 470 475 480 Val Phe Val Gly Phe Ser Gly Gly Val Trp Arg ValPro Arg Ala Asn 485 490 495 Cys Ser Val Tyr Glu Ser Cys Val Asp Cys ValLeu Ala Arg Asp Pro 500 505 510 His Cys Ala Trp Asp Pro Glu Ser Arg LeuCys Ser Leu Arg Asn Ser 515 520 525 Trp Lys Gln Asp Met Glu Arg Gly AsnPro Glu Trp Ala Cys Ala Ser 530 535 540 Gly Pro Met Ser Arg Ser Leu ArgPro Gln Ser Arg Pro Gln Ile Val 545 550 555 560 Lys Glu Val Leu Ala ValPro Asn Ser Ile Leu Glu Leu Pro Cys Pro 565 570 575 His Leu Ser Ala LeuAla Ser Tyr Tyr Trp Ser His Gly Pro Ala Ala 580 585 590 Val Pro Glu AlaSer Ser Thr Val Tyr Asn Gly Ser Leu Leu Leu Ile 595 600 605 Val Gln AspGly Val Gly Gly Leu Tyr Gln Cys Trp Ala Thr Glu Asn 610 615 620 Gly PheSer Tyr Pro Val Ile Ser Tyr Trp Val Asp Ser Gln Asp Gln 625 630 635 640Thr Leu Ala Leu Asp Pro Glu Leu Ala Gly Ile Pro Arg Glu His Val 645 650655 Lys Val Pro Leu Thr Arg Val Ser Gly Gly Ala Ala Leu Ala Ala Gln 660665 670 Gln Ser Tyr Trp Pro His Phe Val Thr Val Thr Val Leu Phe Ala Leu675 680 685 Val Leu Ser Gly Ala Leu Ile Ile Leu Val Ala Ser Pro Leu ArgAla 690 695 700 Leu Arg Ala Arg Gly Lys Val Gln Gly Cys Glu Thr Leu ArgPro Gly 705 710 715 720 Glu Lys Ala Pro Leu Ser Arg Glu Gln His Leu GlnSer Pro Lys Glu 725 730 735 Cys Arg Thr Ser Ala Ser Asp Val Asp Ala AspAsn Asn Cys Leu Gly 740 745 750 Thr Glu Val Ala 755 9 2281 DNA Homosapiens 9 gcctgtgcct agagtttaag ctacctcagt gcctaggcag ttgttgtcagcgtccacatc 60 actggcagag gtcctgcatt ccttgggaga ctggaggtgt tgctctctgcttaacggggc 120 cttctcccca gggcgcaggg tctcacagcc ctgaaccttg ccccgagcccggagtgctct 180 caatggggag gccacgagga tgatgagggc tcctgaaagc actaaggcaaagaggacagt 240 gacagtgaca aagtggggcc agtaggactg ctgggcagcc agggcggccccaccactgac 300 cctggtcaac gggaccttca catgctcccg ggggatgcct gccagttcaggatccagggc 360 cagggtctgg tcctggctgt ccacccagta ggagatcaca gggtatgaaaagccattctc 420 agttgcccag cactggtaga gacccccaac tccatcctgc actatcagcaagagggagcc 480 attgtagaca gtggaagagg cttctgggac tgctgctggg ccatgactccaataataaga 540 ggccaaggct gacaggtggg ggcaggggag ctccaggatg gagttggggacagccaggac 600 ttctttaatg atttgcgggc ggctctgagg ccgaaggctc ctgctcatggggccactggc 660 acatgcccac tctgggttcc cccgctccat gtcctgcttc caggagttcaggttgggggc 720 agacaggagg caacaggttc gggactcagg gtcccaggca cagtgggggtcccgggcaag 780 gacacagtcc acacagctct catagacact acagttggct cggggcaccctccagacacc 840 tcctgagaag cctacaaaca ctgcaccctg ggtgggggcc agctgcaggttgcgaacagg 900 ttcagggtca gggaacagct gaatctcttc caccagatga gcactgctgtccccacttac 960 cacagccttg tggagcgacc ctgtggtggt tcccaggtac atgacaagatggctgtgccc 1020 atcaaggccc tgggctgtct ccactgcaag ccgtgtatac tccacgccagatttcaccag 1080 caggggcgtc cccaccactt gctcatccat caggaaatgg tccttcatgaaggtcagggc 1140 cttatcagag gaggggccca ctgagcaact gcctggccgg gggttggtctcagggcccct 1200 ataagtagtc cagcgtgaag tttctttgtt caactctttg tatttccccttaaagacacg 1260 ttcaatgtcc aagagagaga aggcacaaac cgcagagctc ctggtcccgccaacctgcca 1320 ctgggaggtg aagactgcgt agatgtgggg agctgtggga gaatcggcggggagcaggac 1380 cgcgtggcgg atgacgttga agggcagctg ccccggctgg gtgcagagcagctgggcctt 1440 caggaaggtg gtccacttct tctgcagcag cttttcgccg cccacgtcattcttgcagac 1500 tctagccacc cgcgatgtgt ggagcctctc aaagaagtca aactcgctggctgtctcctc 1560 gaagaagaag tagacgacct gggtcgaagg gatggctgcc acaaaggaggcgtcatgatg 1620 cagccagcgg aggaagttgt cggtcttgag gacaggctgg gatcccagtgtgcgcatcag 1680 gatgggctca ctgcccagga agttgttcat agtaccagaa tagagcatcccatccaccaa 1740 gacagccgta tgcttgtgag cggggtcaaa ggggctttgg ccttttccctccatgacctt 1800 gtcctccgag atgggcaaca ggtaggaatc ttgaagttca atgaaggtacaagcagggct 1860 gaaggcgaag gtgccgcagg tgtagagatg ggtgacattg taagaaaccaggacacggat 1920 gaagttgaaa cactgtgtct cattgctctt cttcttaaag gcacattcactcttttttct 1980 gtcactggct ggccacggta tcatgttctt tagcctgggg acccctggatcctggatatc 2040 caaggccaga atggcttctc gagcccccac gtagagagta tttccatcaccactcaggag 2100 cagagtgtca aaatcctgga ggcccttctg gtggaagaag ctaagtgccctacgttcatc 2160 ccctgcatag tatctgaccc tgggcatggg cccctgcccg cctccccccgcggtcgtcgt 2220 cggcagcagc agctgaagca gttggaagag gaaaaggccc aggaggctccaggggtccag 2280 g 2281 10 754 PRT Homo sapiens 10 Leu Asp Pro Trp SerLeu Leu Gly Leu Phe Leu Phe Gln Leu Leu Gln 1 5 10 15 Leu Leu Leu ProThr Thr Thr Ala Gly Gly Gly Gly Gln Gly Pro Met 20 25 30 Pro Arg Val ArgTyr Tyr Ala Gly Asp Glu Arg Arg Ala Leu Ser Phe 35 40 45 Phe His Gln LysGly Leu Gln Asp Phe Asp Thr Leu Leu Leu Ser Gly 50 55 60 Asp Gly Asn ThrLeu Tyr Val Gly Ala Arg Glu Ala Ile Leu Ala Leu 65 70 75 80 Asp Ile GlnAsp Pro Gly Val Pro Arg Leu Lys Asn Met Ile Pro Trp 85 90 95 Pro Ala SerAsp Arg Lys Lys Ser Glu Cys Ala Phe Lys Lys Lys Ser 100 105 110 Asn GluThr Gln Cys Phe Asn Phe Ile Arg Val Leu Val Ser Tyr Asn 115 120 125 ValThr His Leu Tyr Thr Cys Gly Thr Phe Ala Phe Ser Pro Ala Cys 130 135 140Thr Phe Ile Glu Leu Gln Asp Ser Tyr Leu Leu Pro Ile Ser Glu Asp 145 150155 160 Lys Val Met Glu Gly Lys Gly Gln Ser Pro Phe Asp Pro Ala His Lys165 170 175 His Thr Ala Val Leu Val Asp Gly Met Leu Tyr Ser Gly Thr MetAsn 180 185 190 Asn Phe Leu Gly Ser Glu Pro Ile Leu Met Arg Thr Leu GlySer Gln 195 200 205 Pro Val Leu Lys Thr Asp Asn Phe Leu Arg Trp Leu HisHis Asp Ala 210 215 220 Ser Phe Val Ala Ala Ile Pro Ser Thr Gln Val ValTyr Phe Phe Phe 225 230 235 240 Glu Glu Thr Ala Ser Glu Phe Asp Phe PheGlu Arg Leu His Thr Ser 245 250 255 Arg Val Ala Arg Val Cys Lys Asn AspVal Gly Gly Glu Lys Leu Leu 260 265 270 Gln Lys Lys Trp Thr Thr Phe LeuLys Ala Gln Leu Leu Cys Thr Gln 275 280 285 Pro Gly Gln Leu Pro Phe AsnVal Ile Arg His Ala Val Leu Leu Pro 290 295 300 Ala Asp Ser Pro Thr AlaPro His Ile Tyr Ala Val Phe Thr Ser Gln 305 310 315 320 Trp Gln Val GlyGly Thr Arg Ser Ser Ala Val Cys Ala Phe Ser Leu 325 330 335 Leu Asp IleGlu Arg Val Phe Lys Gly Lys Tyr Lys Glu Leu Asn Lys 340 345 350 Glu ThrSer Arg Trp Thr Thr Tyr Arg Gly Pro Glu Thr Asn Pro Arg 355 360 365 ProGly Ser Cys Ser Val Gly Pro Ser Ser Asp Lys Ala Leu Thr Phe 370 375 380Met Lys Asp His Phe Leu Met Asp Glu Gln Val Val Gly Thr Pro Leu 385 390395 400 Leu Val Lys Ser Gly Val Glu Tyr Thr Arg Leu Ala Val Glu Thr Ala405 410 415 Gln Gly Leu Asp Gly His Ser His Leu Val Met Tyr Leu Gly ThrThr 420 425 430 Thr Gly Ser Leu His Lys Ala Val Val Ser Gly Asp Ser SerAla His 435 440 445 Leu Val Glu Glu Ile Gln Leu Phe Pro Asp Pro Glu ProVal Arg Asn 450 455 460 Leu Gln Leu Ala Pro Thr Gln Gly Ala Val Phe ValGly Phe Ser Gly 465 470 475 480 Gly Val Trp Arg Val Pro Arg Ala Asn CysSer Val Tyr Glu Ser Cys 485 490 495 Val Asp Cys Val Leu Ala Arg Asp ProHis Cys Ala Trp Asp Pro Glu 500 505 510 Ser Arg Thr Cys Cys Leu Leu SerAla Pro Asn Leu Asn Ser Trp Lys 515 520 525 Gln Asp Met Glu Arg Gly AsnPro Glu Trp Ala Cys Ala Ser Gly Pro 530 535 540 Met Ser Arg Ser Leu ArgPro Gln Ser Arg Pro Gln Ile Ile Lys Glu 545 550 555 560 Val Leu Ala ValPro Asn Ser Ile Leu Glu Leu Pro Cys Pro His Leu 565 570 575 Ser Ala LeuAla Ser Tyr Tyr Trp Ser His Gly Pro Ala Ala Val Pro 580 585 590 Glu AlaSer Ser Thr Val Tyr Asn Gly Ser Leu Leu Leu Ile Val Gln 595 600 605 AspGly Val Gly Gly Leu Tyr Gln Cys Trp Ala Thr Glu Asn Gly Phe 610 615 620Ser Tyr Pro Val Ile Ser Tyr Trp Val Asp Ser Gln Asp Gln Thr Leu 625 630635 640 Ala Leu Asp Pro Glu Leu Ala Gly Ile Pro Arg Glu His Val Lys Val645 650 655 Pro Leu Thr Arg Val Ser Gly Gly Ala Ala Leu Ala Ala Gln GlnSer 660 665 670 Tyr Trp Pro His Phe Val Thr Val Thr Val Leu Phe Ala LeuVal Leu 675 680 685 Ser Gly Ala Leu Ile Ile Leu Val Ala Ser Pro Leu ArgAla Leu Arg 690 695 700 Ala Arg Gly Lys Val Gln Gly Cys Glu Thr Leu ArgPro Gly Glu Lys 705 710 715 720 Ala Pro Leu Ser Arg Glu Gln His Leu GlnSer Pro Lys Glu Cys Arg 725 730 735 Thr Ser Ala Ser Asp Val Asp Ala AspAsn Asn Cys Leu Gly Thr Glu 740 745 750 Val Ala 11 6408 DNA Homo sapiens11 cctgggactc tgggagaatg gtccagagct cattgtcctt gttgataaaa tgatagattt 60ggactcaata tcccatgctg cctcttccaa cttgattttt accccagact gggctaccag 120actggtatgc ccacacatgc ccgtttcctt tcttttcttc tctgcatctc tgcctttgtg 180tccagagcgt gttttccctt tgcaagtttc tctccattct gcacattatg agtttcagca 240tttctgttgc cctagaaagt ctatctttga gatcttgcac tgtttctctt tttacagtgt 300ctcataaact cccttcttgg attcagaacc accctttctt tcccattatc ctgtcaaact 360gcttcttgcc atggtccagg ggtaggagga tggcaggcag gaggtgcttc tctggggctc 420ttagtgtctc aattcttctg ctttatctgg gttttccttt acccagaatt ttattatgta 480aaatgcttca ctcagacttt gttctaatta tccaattttt ggcatactct agaaagtctt 540ttgatatttt ccttcctcca acttatctat ttttatttca tagttctctt tggttatctc 600ttagaatcac actttcctgg ttttaatttt tcaaatcctt tgtctttctc actcgttctt 660aggtcacctt tttttacatt ttcaaatata ttttttgttc agcagagggc tcccttccca 720tccctcttgc agcccgggca gctaggattt gaagcttgcc ccttgaatct ttctctcccg 780ccttctagcc atcagaaaca ctagatcact taaacttgta aacaattcgg cctcgctcct 840tgtgattgcg ctaaaccttc cgtcctcagc tgagaacgct ccaccacctc cccggatcgc 900tcatctcttg gctgccctcc cactgttcct gatgttattt tactccccgt atcccctact 960cgttcttcac aattctgtag ggtgcgtatt actaacccca gtttacagct gaggaaactg 1020aggcttggag aggttcgctc ggtatcgtac agtttgcaag gttaacccta atccggccag 1080ttctggcttt ccagcccagc ccagcagcct agcctccctc tctgccgctg caggttataa 1140cggctctccc ccgttttaca cgaggtccct tccccttcaa atccacaggc aggaagatcg 1200ttccgaactg acggggctgg ggaatgtggg agtccggagt ggggtttggg ggagcttcct 1260caggccctga gtgttggggt gggcaggccg cgccgatggc cctcggggat gtcacattcg 1320agatggggtg accgagaacg gcaaggcggg atgtggcaaa cggcggcaag tgctcggagt 1380cctaggtctt gccgccggaa tgccggccgg ggaaggggct tcggcccacc gggctggtca 1440ccacactcgg caggcccggg gcgggagtcg gccgagcagc cgcgggatgc agggcgcccc 1500ctcgcgctcc tccgcgcgcc tcgaggctgg cgggtgcagc gcccgccgcg gcaggtctgc 1560tccagccccc tcctcttttt cgctcccgct cccctccttc tctccctttg cttgcaactc 1620ctcccccacc gccccctccc tccttctgct cccgcggtct cctcctccct gctctctccg 1680agcgccgggt cgggagctag ttggagcgcg ggggttggtg ccagagccca gctccgccga 1740gccgggcggg tcggcagcgc atccagcggc tgctgggagc ccgagcgcag cgggcgcggg 1800cccgggtggg gactgcaccg gagcgctgag agctggaggc cgttcctgcg cggccgcccc 1860attcccagac cggccgccag cccatctggt tagctcccgc cgctccgcgc cgcccgggag 1920tcgggagccg cggggaaccg ggcacctgca cccgcctctg ggagtgagtg gttccagctg 1980gtgcctggcc tgtgtctctt ggatgccctg tggcttcagt ccgtctcctg ttgcccacca 2040cctcgtccct gggccgcctg ataccccagc ccaacagcta aggtgtggat ggacagtagg 2100gggctggctt ctctcactgg tcaggggtct tctcccctgt ctgcctcccg gagctaggac 2160tgcagagggg cctatcatgg tgcttgcagg ccccctggct gtctcgctgt tgctgcccag 2220cctcacactg ctggtgtccc acctctccag ctcccaggat gtctccagtg agcccagcag 2280tgagcagcag ctgtgcgccc ttagcaagca ccccaccgtg gcctttgaag acctgcagcc 2340gtgggtctct aacttcacct accctggagc ccgggatttc tcccagctgg ctttggaccc 2400ctccgggaac cagctcatcg tgggagccag gaactacctc ttcagactca gccttgccaa 2460tgtctctctt cttcaggcca cagagtgggc ctccagtgag gacacgcgcc gctcctgcca 2520aagcaaaggg aagactgagg aggagtgtca gaactacgtg cgagtcctga tcgtcgccgg 2580ccggaaggtg ttcatgtgtg gaaccaatgc cttttccccc atgtgcacca gcagacaggt 2640ggggaacctc agccggacta ctgagaagat caatggtgtg gcccgctgcc cctatgaccc 2700acgccacaac tccacagctg tcatctcctc ccagggggag ctctatgcag ccacggtcat 2760cgacttctca ggtcgggacc ctgccatcta ccgcagcctg ggcagtgggc caccgcttcg 2820cactgcccaa tataactcca agtggcttaa tgagccaaac ttcgtggcag cctatgatat 2880tgggctgttt gcatacttct tcctgcggga gaacgcagtg gagcacgact gtggacgcac 2940cgtgtactct cgcgtggccc gcgtgtgcaa gaatgacgtg gggggccgat tcctgctgga 3000ggacacatgg accacattca tgaaggcccg gctcaactgc tcccgcccgg gcgaggtccc 3060cttctactat aacgagctgc agagtgcctt ccacttgcca gagcaggacc tcatctatgg 3120agttttcaca accaacgtaa acagcatcgc ggcttctgct gtctgcgcct tcaacctcag 3180tgctatctcc caggctttca atggcccatt tcgctaccag gagaacccca gggctgcctg 3240gctccccata gccaacccca tccccaattt ccagtgtggc accctgcctg agaccggtcc 3300caacgagaac ctgacggagc gcagcctgca ggacgcgcag cgcctcttcc tgatgagcga 3360ggccgtgcag ccggtgacac ccgagccctg tgtcacccag gacagcgtgc gcttctcaca 3420cctcgtggtg gacctggtgc aggctaaaga cacgctctac catgtactct acattggcac 3480cgagtcgggc accatcctga aggcgctgtc cacggcgagc cgcagcctcc acggctgcta 3540cctggaggag ctgcacgtgc tgccccccgg gcgccgcgag cccctgcgca gcctgcgcat 3600cctgcacagc gcccgcgcgc tcttcgtggg gctgagagac ggcgtcctgc gggtcccact 3660ggagaggtgc gccgcctacc gcagccaggg ggcatgcctg ggggcccggg acccgtactg 3720tggctgggac gggaagcagc aacgttgcag cacactcgag gacagctcca acatgagcct 3780ctggacccag aacatcaccg cctgtcctgt gcggaatgtg acacgggatg ggggcttcgg 3840cccatggtca ccatggcaac catgtgagca cttggatggg gacaactcag gctcttgcct 3900gtgtcgagct cgatcctgtg attcccctcg accccgctgt gggggccttg actgcctggg 3960gccagccatc cacatcgcca actgctccag gaatggggcg tggaccccgt ggtcatcgtg 4020ggcgctgtgc agcacgtcct gtggcatcgg cttccaggtc cgccagcgaa gttgcagcaa 4080ccctgctccc cgccacgggg gccgcatctg cgtgggcaag agccgggagg aacggttctg 4140taatgagaac acgccttgcc cggtgcccat cttctgggct tcctggggct cctggagcaa 4200gtgcagcagc aactgtggag ggggcatgca gtcgcggcgt cgggcctgcg agaacggcaa 4260ctcctgcctg ggctgcggcg tggagttcaa gacgtgcaac cccgagggct gccccgaagt 4320gcggcgcaac accccctgga cgccgtggct gcccgtgaac gtgacgcagg gcggggcacg 4380gcaggagcag cggttccgct tcacctgccg cgcgcccctt gcagacccgc acggcctgca 4440gttcggcagg agaaggaccg agacgaggac ctgtcccgcg gacggctccg gctcctgcga 4500caccgacgcc ctggtggagg acctcctgcg cagcgggagc acctccccgc acacggtgag 4560cgggggctgg gccgcctggg gcccgtggtc gtcctgctcc cgggactgcg agctgggctt 4620ccgcgtccgc aagagaacgt gcactaaccc ggagccccgc aacgggggcc tgccctgcgt 4680gggcgatgct gccgagtacc aggactgcaa cccccaggct tgcccagttc ggggtgcttg 4740gtcctgctgg acctcatggt ctccatgctc agcttcctgt ggtgggggtc actatcaacg 4800cacccgttcc tgcaccagcc ccgcaccctc cccaggtgag gacatctgtc tcgggctgca 4860cacggaggag gcactatgtg ccacacaggc ctgcccagaa ggctggtcgc cctggtctga 4920gtggagtaag tgcactgacg acggagccca gagccgaagc cggcactgtg aggagctcct 4980cccagggtcc agcgcctgtg ctggaaacag cagccagagc cgcccctgcc cctacagcga 5040gattcccgtc atcctgccag cctccagcat ggaggaggcc accggctgtg cagggttcaa 5100tctcatccac ttggtggcca cgggcatctc ctgcttcttg ggctctgggc tcctgaccct 5160agcagtgtac ctgtcttgcc agcactgcca gcgtcagtcc caggagtcca cactggtcca 5220tcctgccacc cccaaccatt tgcactacaa gggcggaggc accccgaaga atgaaaagta 5280cacacccatg gaattcaaga ccctgaacaa gaataacttg atccctgatg acagagccaa 5340cttctaccca ttgcagcaga ccaatgtgta cacgactact tactacccaa gccccctgaa 5400caaacacagc ttccggcccg aggcctcacc tggacaacgg tgcttcccca acagctgata 5460ccgccgtcct ggggacttgg gcttcttgcc ttcataaggc acagagcaga tggagatggg 5520acagtggagc cagtttggtt ttctccctct gcactaggcc aagaacttgc tgccttgcct 5580gtggggggtc ccatccggct tcagagagct ctggctggca ttgaccatgg gggaaagggc 5640tggtttcagg ctgacatatg gccgcaggtc cagttcagcc caggtctctc atggttatct 5700tccaacccac tgtcacgctg acactatgct gccatgcctg ggctgtggac ctactgggca 5760tttgaggaac tggagaatgg agatggcaag agggcaggct tttaagtttg ggttggagac 5820aacttcctgt ggcccccaca agctgagtct ggccttctcc agctggcccc aaaaaaggcc 5880tttgctacat cctgattatc tctgaaagta atcaatcaag tggctccagt agctctggat 5940tttctgccag ggctgggcca ttgtggtgct gccccagtat gacatgggac caaggccagc 6000gcaggttatc cacctctgcc tggaagtcta tactctaccc agggcatccc tctggtcaga 6060ggcagtgagt actgggaact ggaggctgac ctgtgcttag aagtccttta atctgggctg 6120gtacaggcct cagccttgcc ctcaatgcac gaaaggtggc ccaggagaga ggatcaatgc 6180cacaggaggc agaagtctgg cctctgtgcc tctatggaga ctatcttcca gttgctgctc 6240aacagagttg ttggctgaga cctgcttggg agtctctgct ggcccttcat ctgttcagga 6300acacacacac acacacactc acacacgcac acacaatcac aatttgctac agcaacaaaa 6360aagacattgg gctgtggcat tattaattaa agatgatatc cagtctcc 6408 12 1352 PRTHomo sapiens 12 Met Pro Ala Gly Glu Gly Ala Ser Ala His Arg Ala Gly HisHis Thr 1 5 10 15 Arg Gln Ala Arg Gly Gly Ser Arg Pro Ser Ser Arg GlyMet Gln Gly 20 25 30 Ala Pro Ser Arg Ser Ser Ala Arg Leu Glu Ala Gly GlyCys Ser Ala 35 40 45 Arg Arg Gly Arg Ser Ala Pro Ala Pro Ser Ser Phe SerLeu Pro Leu 50 55 60 Pro Ser Phe Ser Pro Phe Ala Cys Asn Ser Ser Pro ThrAla Pro Ser 65 70 75 80 Leu Leu Leu Leu Pro Arg Ser Pro Pro Pro Cys SerLeu Arg Ala Pro 85 90 95 Gly Arg Glu Leu Val Gly Ala Arg Gly Leu Val ProGlu Pro Ser Ser 100 105 110 Ala Glu Pro Gly Gly Ser Ala Ala His Pro AlaAla Ala Gly Ser Pro 115 120 125 Ser Ala Ala Gly Ala Gly Pro Gly Gly AspCys Thr Gly Ala Leu Arg 130 135 140 Ala Gly Gly Arg Ser Cys Ala Ala AlaPro Phe Pro Asp Arg Pro Pro 145 150 155 160 Ala His Leu Val Ser Ser ArgArg Ser Ala Pro Pro Gly Ser Arg Glu 165 170 175 Pro Arg Gly Thr Gly HisLeu His Pro Pro Leu Gly Val Ser Gly Ser 180 185 190 Ser Trp Cys Leu AlaCys Val Ser Trp Met Pro Cys Gly Phe Ser Pro 195 200 205 Ser Pro Val AlaHis His Leu Val Pro Gly Pro Pro Asp Thr Pro Ala 210 215 220 Gln Gln LeuArg Cys Gly Trp Thr Val Gly Gly Trp Leu Leu Ser Leu 225 230 235 240 ValArg Gly Leu Leu Pro Cys Leu Pro Pro Gly Ala Arg Thr Ala Glu 245 250 255Gly Pro Ile Met Val Leu Ala Gly Pro Leu Ala Val Ser Leu Leu Leu 260 265270 Pro Ser Leu Thr Leu Leu Val Ser His Leu Ser Ser Ser Gln Asp Val 275280 285 Ser Ser Glu Pro Ser Ser Glu Gln Gln Leu Cys Ala Leu Ser Lys His290 295 300 Pro Thr Val Ala Phe Glu Asp Leu Gln Pro Trp Val Ser Asn PheThr 305 310 315 320 Tyr Pro Gly Ala Arg Asp Phe Ser Gln Leu Ala Leu AspPro Ser Gly 325 330 335 Asn Gln Leu Ile Val Gly Ala Arg Asn Tyr Leu PheArg Leu Ser Leu 340 345 350 Ala Asn Val Ser Leu Leu Gln Ala Thr Glu TrpAla Ser Ser Glu Asp 355 360 365 Thr Arg Arg Ser Cys Gln Ser Lys Gly LysThr Glu Glu Glu Cys Gln 370 375 380 Asn Tyr Val Arg Val Leu Ile Val AlaGly Arg Lys Val Phe Met Cys 385 390 395 400 Gly Thr Asn Ala Phe Ser ProMet Cys Thr Ser Arg Gln Val Gly Asn 405 410 415 Leu Ser Arg Thr Thr GluLys Ile Asn Gly Val Ala Arg Cys Pro Tyr 420 425 430 Asp Pro Arg His AsnSer Thr Ala Val Ile Ser Ser Gln Gly Glu Leu 435 440 445 Tyr Ala Ala ThrVal Ile Asp Phe Ser Gly Arg Asp Pro Ala Ile Tyr 450 455 460 Arg Ser LeuGly Ser Gly Pro Pro Leu Arg Thr Ala Gln Tyr Asn Ser 465 470 475 480 LysTrp Leu Asn Glu Pro Asn Phe Val Ala Ala Tyr Asp Ile Gly Leu 485 490 495Phe Ala Tyr Phe Phe Leu Arg Glu Asn Ala Val Glu His Asp Cys Gly 500 505510 Arg Thr Val Tyr Ser Arg Val Ala Arg Val Cys Lys Asn Asp Val Gly 515520 525 Gly Arg Phe Leu Leu Glu Asp Thr Trp Thr Thr Phe Met Lys Ala Arg530 535 540 Leu Asn Cys Ser Arg Pro Gly Glu Val Pro Phe Tyr Tyr Asn GluLeu 545 550 555 560 Gln Ser Ala Phe His Leu Pro Glu Gln Asp Leu Ile TyrGly Val Phe 565 570 575 Thr Thr Asn Val Asn Ser Ile Ala Ala Ser Ala ValCys Ala Phe Asn 580 585 590 Leu Ser Ala Ile Ser Gln Ala Phe Asn Gly ProPhe Arg Tyr Gln Glu 595 600 605 Asn Pro Arg Ala Ala Trp Leu Pro Ile AlaAsn Pro Ile Pro Asn Phe 610 615 620 Gln Cys Gly Thr Leu Pro Glu Thr GlyPro Asn Glu Asn Leu Thr Glu 625 630 635 640 Arg Ser Leu Gln Asp Ala GlnArg Leu Phe Leu Met Ser Glu Ala Val 645 650 655 Gln Pro Val Thr Pro GluPro Cys Val Thr Gln Asp Ser Val Arg Phe 660 665 670 Ser His Leu Val ValAsp Leu Val Gln Ala Lys Asp Thr Leu Tyr His 675 680 685 Val Leu Tyr IleGly Thr Glu Ser Gly Thr Ile Leu Lys Ala Leu Ser 690 695 700 Thr Ala SerArg Ser Leu His Gly Cys Tyr Leu Glu Glu Leu His Val 705 710 715 720 LeuPro Pro Gly Arg Arg Glu Pro Leu Arg Ser Leu Arg Ile Leu His 725 730 735Ser Ala Arg Ala Leu Phe Val Gly Leu Arg Asp Gly Val Leu Arg Val 740 745750 Pro Leu Glu Arg Cys Ala Ala Tyr Arg Ser Gln Gly Ala Cys Leu Gly 755760 765 Ala Arg Asp Pro Tyr Cys Gly Trp Asp Gly Lys Gln Gln Arg Cys Ser770 775 780 Thr Leu Glu Asp Ser Ser Asn Met Ser Leu Trp Thr Gln Asn IleThr 785 790 795 800 Ala Cys Pro Val Arg Asn Val Thr Arg Asp Gly Gly PheGly Pro Trp 805 810 815 Ser Pro Trp Gln Pro Cys Glu His Leu Asp Gly AspAsn Ser Gly Ser 820 825 830 Cys Leu Cys Arg Ala Arg Ser Cys Asp Ser ProArg Pro Arg Cys Gly 835 840 845 Gly Leu Asp Cys Leu Gly Pro Ala Ile HisIle Ala Asn Cys Ser Arg 850 855 860 Asn Gly Ala Trp Thr Pro Trp Ser SerTrp Ala Leu Cys Ser Thr Ser 865 870 875 880 Cys Gly Ile Gly Phe Gln ValArg Gln Arg Ser Cys Ser Asn Pro Ala 885 890 895 Pro Arg His Gly Gly ArgIle Cys Val Gly Lys Ser Arg Glu Glu Arg 900 905 910 Phe Cys Asn Glu AsnThr Pro Cys Pro Val Pro Ile Phe Trp Ala Ser 915 920 925 Trp Gly Ser TrpSer Lys Cys Ser Ser Asn Cys Gly Gly Gly Met Gln 930 935 940 Ser Arg ArgArg Ala Cys Glu Asn Gly Asn Ser Cys Leu Gly Cys Gly 945 950 955 960 ValGlu Phe Lys Thr Cys Asn Pro Glu Gly Cys Pro Glu Val Arg Arg 965 970 975Asn Thr Pro Trp Thr Pro Trp Leu Pro Val Asn Val Thr Gln Gly Gly 980 985990 Ala Arg Gln Glu Gln Arg Phe Arg Phe Thr Cys Arg Ala Pro Leu Ala 9951000 1005 Asp Pro His Gly Leu Gln Phe Gly Arg Arg Arg Thr Glu Thr ArgThr 1010 1015 1020 Cys Pro Ala Asp Gly Ser Gly Ser Cys Asp Thr Asp AlaLeu Val Glu 1025 1030 1035 1040 Asp Leu Leu Arg Ser Gly Ser Thr Ser ProHis Thr Val Ser Gly Gly 1045 1050 1055 Trp Ala Ala Trp Gly Pro Trp SerSer Cys Ser Arg Asp Cys Glu Leu 1060 1065 1070 Gly Phe Arg Val Arg LysArg Thr Cys Thr Asn Pro Glu Pro Arg Asn 1075 1080 1085 Gly Gly Leu ProCys Val Gly Asp Ala Ala Glu Tyr Gln Asp Cys Asn 1090 1095 1100 Pro GlnAla Cys Pro Val Arg Gly Ala Trp Ser Cys Trp Thr Ser Trp 1105 1110 11151120 Ser Pro Cys Ser Ala Ser Cys Gly Gly Gly His Tyr Gln Arg Thr Arg1125 1130 1135 Ser Cys Thr Ser Pro Ala Pro Ser Pro Gly Glu Asp Ile CysLeu Gly 1140 1145 1150 Leu His Thr Glu Glu Ala Leu Cys Ala Thr Gln AlaCys Pro Glu Gly 1155 1160 1165 Trp Ser Pro Trp Ser Glu Trp Ser Lys CysThr Asp Asp Gly Ala Gln 1170 1175 1180 Ser Arg Ser Arg His Cys Glu GluLeu Leu Pro Gly Ser Ser Ala Cys 1185 1190 1195 1200 Ala Gly Asn Ser SerGln Ser Arg Pro Cys Pro Tyr Ser Glu Ile Pro 1205 1210 1215 Val Ile LeuPro Ala Ser Ser Met Glu Glu Ala Thr Gly Cys Ala Gly 1220 1225 1230 PheAsn Leu Ile His Leu Val Ala Thr Gly Ile Ser Cys Phe Leu Gly 1235 12401245 Ser Gly Leu Leu Thr Leu Ala Val Tyr Leu Ser Cys Gln His Cys Gln1250 1255 1260 Arg Gln Ser Gln Glu Ser Thr Leu Val His Pro Ala Thr ProAsn His 1265 1270 1275 1280 Leu His Tyr Lys Gly Gly Gly Thr Pro Lys AsnGlu Lys Tyr Thr Pro 1285 1290 1295 Met Glu Phe Lys Thr Leu Asn Lys AsnAsn Leu Ile Pro Asp Asp Arg 1300 1305 1310 Ala Asn Phe Tyr Pro Leu GlnGln Thr Asn Val Tyr Thr Thr Thr Tyr 1315 1320 1325 Tyr Pro Ser Pro LeuAsn Lys His Ser Phe Arg Pro Glu Ala Ser Pro 1330 1335 1340 Gly Gln ArgCys Phe Pro Asn Ser 1345 1350 13 3868 DNA Homo sapiens 13 cgactatccatgaagcccgg agccccagtg gctgcaaggc ctgctgcctg aggttctttc 60 aagaaactcaaacctcttag gcctgagtgt gtatgttggg cgggggtccc ctttttattt 120 ctcaaatgatttcctgttgc gcagaggtag tggtgggtct ggaggccagg gagggcttcc 180 cggagcctgtttagccttca gccaactcaa ctcctccccg cttcccaggg agacctgtgg 240 tcttttaggcagaggccaag tgtggggact taggtccacc tccaaagaga aggggaagga 300 gggcaccggggctcctggaa ggcctgatga ggagtcctgt ggcctctcct gctgcgggcc 360 cctctggtttgctttctctg gctgtgattt ctgaccatgt cttttccctc agcaggacag 420 ctggcctgaagctcagagcc ggggcgtgcg ccatggcccc acactgggct gtctggctgc 480 tggcagcaaggctgtggggc ctgggcattg gggctgaggt gtggtggaac cttgtgccgc 540 gtaagacagtgtcttctggg gagctggcca cggtagtacg gcggttctcc cagaccggca 600 tccaggacttcctgacactg acgctgacgg agcccactgg gcttctgtac gtgggcgccc 660 gagaggcgctgtttgccttc agtgtagagg ctctggagct gcaaggagcg atctcctggg 720 aggcccccgtggagaagaag actgagtgta tccagaaagg gaagaacaac cagaccgagt 780 gcttcaacttcatccgcttc ctgcagccct acaatgcctc ccacctgtac gtctgtggca 840 cctacgccttccagcccaag tgcacctacg tcaacatgct caccttcact ttggagcatg 900 gagagtttgaagatgggaag ggcaagtgtc cctatgaccc agctaagggc catgctggcc 960 ttcttgtggatggtgagctg tactcggcca cactcaacaa cttcctgggc acggaaccca 1020 ttatcctgcgtaacatgggg ccccaccact ccatgaagac agagtacctg gccttttggc 1080 tcaacgaacctcactttgta ggctctgcct atgtacctga gagtgtgggc agcttcacgg 1140 gggacgacgacaaggtctac ttcctcttca gggagcgggc agtggagtcc gcctgctatg 1200 ccgagcaggtggtggctcgt gtggcccgtg tctgcaaggg cgatatgggg ggcgcacgga 1260 ccctgcagaggaagtggacc acgttcctga aggcgcggct ggcatgctct gccccgaact 1320 ggcagctctacttcaaccag ctgcaggcga tgcacaccct gcaggacacc tcctggcaca 1380 acaccaccttctttggggtt tttcaagcac agtggggtga catgtacctg tcggccatct 1440 gtgagtaccagttggaagag atccagcggg tgtttgaggg cccctataag gagtaccatg 1500 aggaagcccagaagtgggac cgctacactg accctgtacc cagccctcgg cctggctcgt 1560 gcattaacaactggcatcgg cgccacggct acaccagctc cctggagcta cccgacaaca 1620 tcctcaacttcgtcaagaag cacccgctga tggaggagca ggtggggcct cggtggagcc 1680 gccccctgctcgtgaagaag ggcaccaact tcacccacct ggtggccgac cgggttacag 1740 gacttgatggagccacctat acagtgctgt tcattggcac aggtcaggca tggctgctca 1800 aggctgtgagcctggggccc tgggttcacc tgattgagga gctgcagctg tttgaccagg 1860 agcccatgagaagcctggtg ctatctcagt cgcagaagct gctctttgcc ggctcccgct 1920 ctcagctggtgcagctgccc gtggccgact gcatgaagta tcgctcctgt gcagactgtg 1980 tcctcgcccgggacccctat tgcgcctgga gcgtcaacac cagccgctgt gtggccgtgg 2040 gtggccactctgggtccttt ctgatccagc atgtgatgac ctcggacact tcaggcatct 2100 gcaacctccgtggcagtaag aaagtcaggc ccactcccaa aaacatcacg gtggtggcgg 2160 gcacagacctggtgctgccc tgccacctct cctccaactt ggcccatgcc cgctggacct 2220 ttgggggccgggacctgcct gcggaacagc ccgggtcctt cctctacgat gcccggctcc 2280 aggccctggttgtgatggct gcccagcccc gccatgccgg ggcctaccac tgcttttcag 2340 aggagcagggggcgcggctg gctgctgaag gctaccttgt ggctgtcgtg gcaggcccgt 2400 cggtgaccttggaggcccgg gcccccctgg aaaacctggg gctggtgtgg ctggcggtgg 2460 tggccctgggggctgtgtgc ctggtgctgc tgctgctggt gctgtcattg cgccggcggc 2520 tgcgggaagagctggagaaa ggggccaagg ctactgagag gaccttggtg taccccctgg 2580 agctgcccaaggagcccacc agtcccccct tccggccctg tcctgaacca gatgagaaac 2640 tttgggatcctgtcggttac tactattcag atggctccct taagatagta cctgggcatg 2700 cccggtgccagcccggtggg gggccccctt cgccacctcc aggcatccca ggccagcctc 2760 tgccttctccaactcggctt cacctggggg gtgggcggaa ctcaaatgcc aatggttacg 2820 tgcgcttacaactaggaggg gaggaccggg gagggctcgg gcaccccctg cctgagctcg 2880 cggatgaactgagacgcaaa ctgcagcaac gccagccact gcccgactcc aaccccgagg 2940 agtcatcagtatgaggggaa cccccaccgc gtcggcggga agcgtgggag gtgtagctcc 3000 tacttttgcacaggcaccag ctatctcagg gacatggcac gggcacctgc tctgtctggg 3060 acagatactgcccagcaccc acccggccat gaggacctgc tctgctcagc acgggcactg 3120 ccacttggtgtggctcacca gggcaccagc ctcgcagaag gcatcttcct cctctctgtg 3180 aatcacagacacgcgggacc ccagccgcca aaacttttca aggcagaagt ttcaagatgt 3240 gtgtttgtctgtatttgcac atgtgtttgt gtgtgtgtgt atgtgtgtgt gcacgcgcgt 3300 gcgcgcttgtggcatagctt cctgtttctg tcaagtcttc ccttggcctg ggtcctcctg 3360 gtgagtcattggagctatga aggggaaggg gtcgtatcac tttgtctctc ctacccccac 3420 tgccccgagtgtcgggcagc gatgtacata tggaggtggg gtggacaggg tgctgtgccc 3480 cttcagagggagtgcagggc ttggggtggg cctagtcctg ctcctagggc tgtgaatgtt 3540 ttcagggtggggggagggag atggagcctc ctgtgtgttt ggggggaagg gtgggtgggg 3600 cctcccacttggccccgggg ttcagtggta ttttatactt gccttcttcc tgtacagggc 3660 tgggaaaggctgtgtgaggg gagagaaggg agagggtggg cctgctgtgg acaatggcat 3720 actctcttccagccctagga ggagggctcc taacagtgta acttattgtg tccccgcgta 3780 tttatttgttgtaaatattt gagtattttt atattgacaa ataaaatgga gaaaaaaaaa 3840 aaaaaaaaaaaaaaagtcgt atcgatgt 3868 14 833 PRT Homo sapiens 14 Met Ala Pro His TrpAla Val Trp Leu Leu Ala Ala Arg Leu Trp Gly 1 5 10 15 Leu Gly Ile GlyAla Glu Val Trp Trp Asn Leu Val Pro Arg Lys Thr 20 25 30 Val Ser Ser GlyGlu Leu Ala Thr Val Val Arg Arg Phe Ser Gln Thr 35 40 45 Gly Ile Gln AspPhe Leu Thr Leu Thr Leu Thr Glu Pro Thr Gly Leu 50 55 60 Leu Tyr Val GlyAla Arg Glu Ala Leu Phe Ala Phe Ser Val Glu Ala 65 70 75 80 Leu Glu LeuGln Gly Ala Ile Ser Trp Glu Ala Pro Val Glu Lys Lys 85 90 95 Thr Glu CysIle Gln Lys Gly Lys Asn Asn Gln Thr Glu Cys Phe Asn 100 105 110 Phe IleArg Phe Leu Gln Pro Tyr Asn Ala Ser His Leu Tyr Val Cys 115 120 125 GlyThr Tyr Ala Phe Gln Pro Lys Cys Thr Tyr Val Asn Met Leu Thr 130 135 140Phe Thr Leu Glu His Gly Glu Phe Glu Asp Gly Lys Gly Lys Cys Pro 145 150155 160 Tyr Asp Pro Ala Lys Gly His Ala Gly Leu Leu Val Asp Gly Glu Leu165 170 175 Tyr Ser Ala Thr Leu Asn Asn Phe Leu Gly Thr Glu Pro Ile IleLeu 180 185 190 Arg Asn Met Gly Pro His His Ser Met Lys Thr Glu Tyr LeuAla Phe 195 200 205 Trp Leu Asn Glu Pro His Phe Val Gly Ser Ala Tyr ValPro Glu Ser 210 215 220 Val Gly Ser Phe Thr Gly Asp Asp Asp Lys Val TyrPhe Leu Phe Arg 225 230 235 240 Glu Arg Ala Val Glu Ser Asp Cys Tyr AlaGlu Gln Val Val Ala Arg 245 250 255 Val Ala Arg Val Cys Lys Gly Asp MetGly Gly Ala Arg Thr Leu Gln 260 265 270 Arg Lys Trp Thr Thr Phe Leu LysAla Arg Leu Ala Cys Ser Ala Pro 275 280 285 Asn Trp Gln Leu Tyr Phe AsnGln Leu Gln Ala Met His Thr Leu Gln 290 295 300 Asp Thr Ser Trp His AsnThr Thr Phe Phe Gly Val Phe Gln Ala Gln 305 310 315 320 Trp Gly Asp MetTyr Leu Ser Ala Ile Cys Glu Tyr Gln Leu Glu Glu 325 330 335 Ile Gln ArgVal Phe Glu Gly Pro Tyr Lys Glu Tyr His Glu Glu Ala 340 345 350 Gln LysTrp Asp Arg Tyr Thr Asp Pro Val Pro Ser Pro Arg Pro Gly 355 360 365 SerCys Ile Asn Asn Trp His Arg Arg His Gly Tyr Thr Ser Ser Leu 370 375 380Glu Leu Pro Asp Asn Ile Leu Asn Phe Val Lys Lys His Pro Leu Met 385 390395 400 Glu Glu Gln Val Gly Pro Arg Trp Ser Arg Pro Leu Leu Val Lys Lys405 410 415 Gly Thr Asn Phe Thr His Leu Val Ala Asp Arg Val Thr Gly LeuAsp 420 425 430 Gly Ala Thr Tyr Thr Val Leu Phe Ile Gly Thr Gly Gln AlaTrp Leu 435 440 445 Leu Lys Ala Val Ser Leu Gly Pro Trp Val His Leu IleGlu Glu Leu 450 455 460 Gln Leu Phe Asp Gln Glu Pro Met Arg Ser Leu ValLeu Ser Gln Ser 465 470 475 480 Gln Lys Leu Leu Phe Ala Gly Ser Arg SerGln Leu Val Gln Leu Pro 485 490 495 Val Ala Asp Cys Met Lys Tyr Arg SerCys Ala Asp Cys Val Leu Ala 500 505 510 Arg Asp Pro Tyr Cys Ala Trp SerVal Asn Thr Ser Arg Cys Val Ala 515 520 525 Val Gly Gly His Ser Gly SerPhe Leu Ile Gln His Val Met Thr Ser 530 535 540 Asp Thr Ser Gly Ile CysAsn Leu Arg Gly Ser Lys Lys Val Arg Pro 545 550 555 560 Thr Pro Lys AsnIle Thr Val Val Ala Gly Thr Asp Leu Val Leu Pro 565 570 575 Cys His LeuSer Ser Asn Leu Ala His Ala Arg Trp Thr Phe Gly Gly 580 585 590 Arg AspLeu Pro Ala Glu Gln Pro Gly Ser Phe Leu Tyr Asp Ala Arg 595 600 605 LeuGln Ala Leu Val Val Met Ala Ala Gln Pro Arg His Ala Gly Ala 610 615 620Tyr His Cys Phe Ser Glu Glu Gln Gly Ala Arg Leu Ala Ala Glu Gly 625 630635 640 Tyr Leu Val Ala Val Val Ala Gly Pro Ser Val Thr Leu Glu Ala Arg645 650 655 Ala Pro Leu Glu Asn Leu Gly Leu Val Trp Leu Ala Val Val AlaLeu 660 665 670 Gly Ala Val Cys Leu Val Leu Leu Leu Leu Val Leu Ser LeuArg Arg 675 680 685 Arg Leu Arg Glu Glu Leu Glu Lys Gly Ala Lys Ala ThrGlu Arg Thr 690 695 700 Leu Val Tyr Pro Leu Glu Leu Pro Lys Glu Pro ThrSer Pro Pro Phe 705 710 715 720 Arg Pro Cys Pro Glu Pro Asp Glu Lys LeuTrp Asp Pro Val Gly Tyr 725 730 735 Tyr Tyr Ser Asp Gly Ser Leu Lys IleVal Pro Gly His Ala Arg Cys 740 745 750 Gln Pro Gly Gly Gly Pro Pro SerPro Pro Pro Gly Ile Pro Gly Gln 755 760 765 Pro Leu Pro Ser Pro Thr ArgLeu His Leu Gly Gly Gly Arg Asn Ser 770 775 780 Asn Ala Asn Gly Tyr ValArg Leu Gln Leu Gly Gly Glu Asp Arg Gly 785 790 795 800 Gly Leu Gly HisPro Leu Pro Glu Leu Ala Asp Glu Leu Arg Arg Lys 805 810 815 Leu Gln GlnArg Gln Pro Leu Pro Asp Ser Asn Pro Glu Glu Ser Ser 820 825 830 Val 152558 DNA Homo sapiens 15 tcagagccgg ggcgtgcgcc atggccccac actgggctgtctggctgctg gcagcaaggc 60 tgtggggcct gggcattggg gctgaggtgt ggtggaaccttgtgccgcgt aagacagtgt 120 cttctgggga gctggccacg gtagtacggc ggttctcccagaccggcatc caggacttcc 180 tgacactgac gctgacggag cccactgggc ttctgtacgtgggcgccagg gaccatgcct 240 ctgcactggg cgtccctgtg ttgctgctgc aggctgtgatctcctgggag gcccccgtgg 300 agaagaagac tgagtgtatc cagaaaggga agaacaaccagaccgagtgc ttcaacttca 360 tccgcttcct gcagccctac aatgcctccc acctgtacgtctgtggcacc tacgccttcc 420 agcccaagtg cacctacgtc aacatgctca ccttcactttggagcatgga gagtttgaag 480 atgggaaggg caagtgtccc tatgacccag ctaagggccatgctggcctt cttgtggatg 540 gtgagctgta ctcggccaca ctcaacaact tcctgggcacggaacccatt atcctgcgta 600 acatggggcc ccaccactcc atgaagacag agtacctggccttttggctc aacgaacctc 660 actttgtagg ctctgcctat gtacctgaga gtgtgggcagcttcacgggg gacgacgaca 720 aggtctactt cttcttcagg gagcgggcag tggagtccgactgctatgcc gagcaggtgg 780 tggctcgtgt ggcccgtgtc tgcaagggcg atatggggggcgcacggacc ctgcagagga 840 agtggaccac gttcctgaag gcgcggctgg catgctctgccccgaactgg cagctctact 900 tcaaccagct gcaggcgatg cacaccctgc aggacacctcctggcacaac accaccttct 960 ttggggtttt tcaagcacag tggggtgaca tgtacctgtcggccatctgt gagtaccagt 1020 tggaagagat ccagcgggtg tttgagggcc cctataaggagtaccatgag gaagcccaga 1080 agtgggaccg ctacactgac cctgtaccca gccctcggcctggctcgtgc attaacaact 1140 ggcatcggcg ccacggctac accagctccc tggagctacccgacaacatc ctcaacttcg 1200 tcaagaagca cccgctgatg gaggagcagg tggggcctcggtggagccgc cccctgctcg 1260 tgaagaaggg caccaacttc acccacctgg tggccgaccgggttacagga cttgatggag 1320 ccacctatac agtgctgttc attggcacag gagacggctggctgctcaag gctgtgagcc 1380 tggggccctg ggttcacctg attgaggagc tgcagctgtttgaccaggag cccatgagaa 1440 gcctggtgct atctcagagc aagaagctgc tctttgccggctcccgctct cagctggtgc 1500 agctgcccgt ggccgactgc atgaagtatc gctcctgtgcagactgtgtc ctcgcccggg 1560 acccctattg cgcctggagc gtcaacacca gccgctgtgtggccgtgggt ggccactctg 1620 gatctctact gatccagcat gtgatgacct cggacacttcaggcatctgc aacctccgtg 1680 gcagtaagaa agtcaggccc actcccaaaa acatcacggtggtggcgggc acagacctgg 1740 tgctgccctg ccacctctcc tccaacttgg cccatgcccgctggaccttt gggggccggg 1800 acctgcctgc ggaacagccc gggtccttcc tctacgatgcccggctccag gccctggttg 1860 tgatggctgc ccagccccgc catgccgggg cctaccactgcttttcagag gagcaggggg 1920 cgcggctggc tgctgaaggc taccttgtgg ctgtcgtggcaggcccgtcg gtgaccttgg 1980 aggcccgggc ccccctggaa aacctggggc tggtgtggctggcggtggtg gccctggggg 2040 ctgtgtgcct ggtgctgctg ctgctggtgc tgtcattgcgccggcggctg cgggaagagc 2100 tggagaaagg ggccaaggct actgagagga ccttggtgtaccccctggag ctgcccaagg 2160 agcccaccag tccccccttc cggccctgtc ctgaaccagatgagaaactt tgggatcctg 2220 tcggttacta ctattcagat ggctccctta agatagtacctgggcatgcc cggtgccagc 2280 ccggtggggg gcccccttcg ccacctccag gcatcccaggccagcctctg ccttctccaa 2340 ctcggcttca cctggggggt gggcggaact caaatgccaatggttacgtg cgcttacaac 2400 taggagggga ggaccgggga gggctcgggc accccctgcctgagctcgcg gatgaactga 2460 gacgcaaact gcagcaacgc cagccactgc ccgactccaaccccgaggag tcatcagtat 2520 gaggggaacc cccaccgcgt cggcgggaag cgtgggag2558 16 833 PRT Homo sapiens 16 Met Ala Pro His Trp Ala Val Trp Leu LeuAla Ala Arg Leu Trp Gly 1 5 10 15 Leu Gly Ile Gly Ala Glu Val Trp TrpAsn Leu Val Pro Arg Lys Thr 20 25 30 Val Ser Ser Gly Glu Leu Ala Thr ValVal Arg Arg Phe Ser Gln Thr 35 40 45 Gly Ile Gln Asp Phe Leu Thr Leu ThrLeu Thr Glu Pro Thr Gly Leu 50 55 60 Leu Tyr Val Gly Ala Arg Asp His AlaSer Ala Leu Gly Val Pro Val 65 70 75 80 Leu Leu Leu Gln Ala Val Ile SerTrp Glu Ala Pro Val Glu Lys Lys 85 90 95 Thr Glu Cys Ile Gln Lys Gly LysAsn Asn Gln Thr Glu Cys Phe Asn 100 105 110 Phe Ile Arg Phe Leu Gln ProTyr Asn Ala Ser His Leu Tyr Val Cys 115 120 125 Gly Thr Tyr Ala Phe GlnPro Lys Cys Thr Tyr Val Asn Met Leu Thr 130 135 140 Phe Thr Leu Glu HisGly Glu Phe Glu Asp Gly Lys Gly Lys Cys Pro 145 150 155 160 Tyr Asp ProAla Lys Gly His Ala Gly Leu Leu Val Asp Gly Glu Leu 165 170 175 Tyr SerAla Thr Leu Asn Asn Phe Leu Gly Thr Glu Pro Ile Ile Leu 180 185 190 ArgAsn Met Gly Pro His His Ser Met Lys Thr Glu Tyr Leu Ala Phe 195 200 205Trp Leu Asn Glu Pro His Phe Val Gly Ser Ala Tyr Val Pro Glu Ser 210 215220 Val Gly Ser Phe Thr Gly Asp Asp Asp Lys Val Tyr Phe Phe Phe Arg 225230 235 240 Glu Arg Ala Val Glu Ser Asp Cys Tyr Ala Glu Gln Val Val AlaArg 245 250 255 Val Ala Arg Val Cys Lys Gly Asp Met Gly Gly Ala Arg ThrLeu Gln 260 265 270 Arg Lys Trp Thr Thr Phe Leu Lys Ala Arg Leu Ala CysSer Ala Pro 275 280 285 Asn Trp Gln Leu Tyr Phe Asn Gln Leu Gln Ala MetHis Thr Leu Gln 290 295 300 Asp Thr Ser Trp His Asn Thr Thr Phe Phe GlyVal Phe Gln Ala Gln 305 310 315 320 Trp Gly Asp Met Tyr Leu Ser Ala IleCys Glu Tyr Gln Leu Glu Glu 325 330 335 Ile Gln Arg Val Phe Glu Gly ProTyr Lys Glu Tyr His Glu Glu Ala 340 345 350 Gln Lys Trp Asp Arg Tyr ThrAsp Pro Val Pro Ser Pro Arg Pro Gly 355 360 365 Ser Cys Ile Asn Asn TrpHis Arg Arg His Gly Tyr Thr Ser Ser Leu 370 375 380 Glu Leu Pro Asp AsnIle Leu Asn Phe Val Lys Lys His Pro Leu Met 385 390 395 400 Glu Glu GlnVal Gly Pro Arg Trp Ser Arg Pro Leu Leu Val Lys Lys 405 410 415 Gly ThrAsn Phe Thr His Leu Val Ala Asp Arg Val Thr Gly Leu Asp 420 425 430 GlyAla Thr Tyr Thr Val Leu Phe Ile Gly Thr Gly Asp Gly Trp Leu 435 440 445Leu Lys Ala Val Ser Leu Gly Pro Trp Val His Leu Ile Glu Glu Leu 450 455460 Gln Leu Phe Asp Gln Glu Pro Met Arg Ser Leu Val Leu Ser Gln Ser 465470 475 480 Lys Lys Leu Leu Phe Ala Gly Ser Arg Ser Gln Leu Val Gln LeuPro 485 490 495 Val Ala Asp Cys Met Lys Tyr Arg Ser Cys Ala Asp Cys ValLeu Ala 500 505 510 Arg Asp Pro Tyr Cys Ala Trp Ser Val Asn Thr Ser ArgCys Val Ala 515 520 525 Val Gly Gly His Ser Gly Ser Leu Leu Ile Gln HisVal Met Thr Ser 530 535 540 Asp Thr Ser Gly Ile Cys Asn Leu Arg Gly SerLys Lys Val Arg Pro 545 550 555 560 Thr Pro Lys Asn Ile Thr Val Val AlaGly Thr Asp Leu Val Leu Pro 565 570 575 Cys His Leu Ser Ser Asn Leu AlaHis Ala Arg Trp Thr Phe Gly Gly 580 585 590 Arg Asp Leu Pro Ala Glu GlnPro Gly Ser Phe Leu Tyr Asp Ala Arg 595 600 605 Leu Gln Ala Leu Val ValMet Ala Ala Gln Pro Arg His Ala Gly Ala 610 615 620 Tyr His Cys Phe SerGlu Glu Gln Gly Ala Arg Leu Ala Ala Glu Gly 625 630 635 640 Tyr Leu ValAla Val Val Ala Gly Pro Ser Val Thr Leu Glu Ala Arg 645 650 655 Ala ProLeu Glu Asn Leu Gly Leu Val Trp Leu Ala Val Val Ala Leu 660 665 670 GlyAla Val Cys Leu Val Leu Leu Leu Leu Val Leu Ser Leu Arg Arg 675 680 685Arg Leu Arg Glu Glu Leu Glu Lys Gly Ala Lys Ala Thr Glu Arg Thr 690 695700 Leu Val Tyr Pro Leu Glu Leu Pro Lys Glu Pro Thr Ser Pro Pro Phe 705710 715 720 Arg Pro Cys Pro Glu Pro Asp Glu Lys Leu Trp Asp Pro Val GlyTyr 725 730 735 Tyr Tyr Ser Asp Gly Ser Leu Lys Ile Val Pro Gly His AlaArg Cys 740 745 750 Gln Pro Gly Gly Gly Pro Pro Ser Pro Pro Pro Gly IlePro Gly Gln 755 760 765 Pro Leu Pro Ser Pro Thr Arg Leu His Leu Gly GlyGly Arg Asn Ser 770 775 780 Asn Ala Asn Gly Tyr Val Arg Leu Gln Leu GlyGly Glu Asp Arg Gly 785 790 795 800 Gly Leu Gly His Pro Leu Pro Glu LeuAla Asp Glu Leu Arg Arg Lys 805 810 815 Leu Gln Gln Arg Gln Pro Leu ProAsp Ser Asn Pro Glu Glu Ser Ser 820 825 830 Val 17 3112 DNA Homo sapiens17 tgctgcgggc ccctctggtt tgctttctct ggctgtgatt tctgaccatg tcttttccct 60cagcaggaca gctggcctga agctcagagc cggggcgtgc gccatggccc cacactgggc 120tgtctggctg ctggcagcaa ggctgtgggg cctgggcatt ggggctgagg tgtggtggaa 180ccttgtgccg cgtaagacag tgtcttctgg ggagctggcc acggtagtac ggcggttctc 240ccagaccggc atccaggact tcctgacact gacgctgacg gagcccactg ggcttctgta 300cgtgggcgcc agggaccatg cctctgcact gggcgtccct gtgttgctgc tgcaggctgt 360gatctcctgg gaggcccccg tggagaagaa gactgagtgt atccagaaag ggaagaacaa 420ccagaccgag tgcttcaact tcatccgctt cctgcagccc tacaatgcct cccacctgta 480cgtctgtggc acctacgcct tccagcccaa gtgcacctac gtcaacatgc tcaccttcac 540tttggagcat ggagagtttg aagatgggaa gggcaagtgt ccctatgacc cagctaaggg 600ccatgctggc cttcttgtgg atggtgagct gtactcggcc acactcaaca acttcctggg 660cacggaaccc attatcctgc gtaacatggg gccccaccac tccatgaaga cagagtacct 720ggccttttgg ctcaacgaac ctcactttgt aggctctgcc tatgtacctg agagtgtggg 780cagcttcacg ggggacgacg acaaggtcta cttcttcttc agggagcggg cagtggagtc 840cgactgctat gccgagcagg tggtggctcg tgtggcccgt gtctgcaagg gcgatatggg 900gggcgcacgg accctgcaga ggaagtggac cacgttcctg aaggcgcggc tggcatgctc 960tgccccgaac tggcagctct acttcaacca gctgcaggcg atgcacaccc tgcaggacac 1020ctcctggcac aacaccacct tctttggggt ttttcaagca cagtggggtg acatgtacct 1080gtcggccatc tgtgagtacc agttggaaga gatccagcgg gtgtttgagg gcccctataa 1140ggagtaccat gaggaagccc agaagtggga ccgctacact gaccctgtac ccagccctcg 1200gcctggctcg tgcattaaca actggcatcg gcgccacggc tacaccagct ccctggagct 1260acccgacaac atcctcaact tcgtcaagaa gcacccgctg atggaggagc aggtggggcc 1320tcggtggagc cgccccctgc tcgtgaagaa gggcaccaac ttcacccacc tggtggccga 1380ccgggttaca ggacttgatg gagccaccta tacagtgctg ttcattggca caggagacgg 1440ctggctgctc aaggctgtga gcctggggcc ctgggttcac ctgattgagg agctgcagct 1500gtttgaccag gagcccatga gaagcctggt gctatctcag agcaagaagc tgctctttgc 1560cggctcccgc tctcagctgg tgcagctgcc cgtggccgac tgcatgaagt atcgctcctg 1620tgcagactgt gtcctcgccc gggaccccta ttgcgcctgg agcgtcaaca ccagccgctg 1680tgtggccgtg ggtggccact ctggatctct actgatccag catgtgatga cctcggacac 1740ttcaggcatc tgcaacctcc gtggcagtaa gaaagtcagg cccactccca aaaacatcac 1800ggtggtggcg ggcacagacc tggtgctgcc ctgccacctc tcctccaact tggcccatgc 1860ccgctggacc tttgggggcc gggacctgcc tgcggaacag cccgggtcct tcctctacga 1920tgcccggctc caggccctgg ttgtgatggc tgcccagccc cgccatgccg gggcctacca 1980ctgcttttca gaggagcagg gggcgcggct ggctgctgaa ggctaccttg tggctgtcgt 2040ggcaggcccg tcggtgacct tggaggcccg ggcccccctg gaaaacctgg ggctggtgtg 2100gctggcggtg gtggccctgg gggctgtgtg cctggtgctg ctgctgctgg tgctgtcatt 2160gcgccggcgg ctgcgggaag agctggagaa aggggccaag gctactgaga ggaccttggt 2220gtaccccctg gagctgccca aggagcccac cagtcccccc ttccggccct gtcctgaacc 2280agatgagaaa ctttgggatc ctgtcggtta ctactattca gatggctccc ttaagatagt 2340acctgggcat gcccggtgcc agcccggtgg ggggccccct tcgccacctc caggcatccc 2400aggccagcct ctgccttctc caactcggct tcacctgggg ggtgggcgga actcaaatgc 2460caatggttac gtgcgcttac aactaggagg ggaggaccgg ggagggctcg ggcaccccct 2520gcctgagctc gcggatgaac tgagacgcaa actgcagcaa cgccagccac tgcccgactc 2580caaccccgag gagtcatcag tatgagggga acccccaccg cgtcggcggg aagcgtggga 2640ggtgtagctc ctacttttgc acaggcacca gctacctcag ggacatggca cgggcacctg 2700ctctgtctgg gacagatact gcccagcacc cacccggcca tgaggacctg ctctgctcag 2760cacgggcact gccacttggt gtggctcacc agggcaccag cctcgcagaa ggcatcttcc 2820tcctctctgt gaatcacaga cacgcgggac cccagccgcc aaaacttttc aaggcagaag 2880tttcaagatg tgtgtttgtc tgtatttgca catgtgtttg tgtgtgtgtg tatgtgtgtg 2940tgcacgcgcg tgcgcgcttg tggcatagcc ttcctgtttc tgtcaagtct tcccttggcc 3000tgggtcctcc tggtgagtca ttggagctat gaaggggaag gggtcgtatc actttgtctc 3060tcctaccccc actgccccga gtgtcgggca gcgatgtaca tatggaggtg gg 3112 18 833PRT Homo sapiens 18 Met Ala Pro His Trp Ala Val Trp Leu Leu Ala Ala ArgLeu Trp Gly 1 5 10 15 Leu Gly Ile Gly Ala Glu Val Trp Trp Asn Leu ValPro Arg Lys Thr 20 25 30 Val Ser Ser Gly Glu Leu Ala Thr Val Val Arg ArgPhe Ser Gln Thr 35 40 45 Gly Ile Gln Asp Phe Leu Thr Leu Thr Leu Thr GluPro Thr Gly Leu 50 55 60 Leu Tyr Val Gly Ala Arg Asp His Ala Ser Ala LeuGly Val Pro Val 65 70 75 80 Leu Leu Leu Gln Ala Val Ile Ser Trp Glu AlaPro Val Glu Lys Lys 85 90 95 Thr Glu Cys Ile Gln Lys Gly Lys Asn Asn GlnThr Glu Cys Phe Asn 100 105 110 Phe Ile Arg Phe Leu Gln Pro Tyr Asn AlaSer His Leu Tyr Val Cys 115 120 125 Gly Thr Tyr Ala Phe Gln Pro Lys CysThr Tyr Val Asn Met Leu Thr 130 135 140 Phe Thr Leu Glu His Gly Glu PheGlu Asp Gly Lys Gly Lys Cys Pro 145 150 155 160 Tyr Asp Pro Ala Lys GlyHis Ala Gly Leu Leu Val Asp Gly Glu Leu 165 170 175 Tyr Ser Ala Thr LeuAsn Asn Phe Leu Gly Thr Glu Pro Ile Ile Leu 180 185 190 Arg Asn Met GlyPro His His Ser Met Lys Thr Glu Tyr Leu Ala Phe 195 200 205 Trp Leu AsnGlu Pro His Phe Val Gly Ser Ala Tyr Val Pro Glu Ser 210 215 220 Val GlySer Phe Thr Gly Asp Asp Asp Lys Val Tyr Phe Phe Phe Arg 225 230 235 240Glu Arg Ala Val Glu Ser Asp Cys Tyr Ala Glu Gln Val Val Ala Arg 245 250255 Val Ala Arg Val Cys Lys Gly Asp Met Gly Gly Ala Arg Thr Leu Gln 260265 270 Arg Lys Trp Thr Thr Phe Leu Lys Ala Arg Leu Ala Cys Ser Ala Pro275 280 285 Asn Trp Gln Leu Tyr Phe Asn Gln Leu Gln Ala Met His Thr LeuGln 290 295 300 Asp Thr Ser Trp His Asn Thr Thr Phe Phe Gly Val Phe GlnAla Gln 305 310 315 320 Trp Gly Asp Met Tyr Leu Ser Ala Ile Cys Glu TyrGln Leu Glu Glu 325 330 335 Ile Gln Arg Val Phe Glu Gly Pro Tyr Lys GluTyr His Glu Glu Ala 340 345 350 Gln Lys Trp Asp Arg Tyr Thr Asp Pro ValPro Ser Pro Arg Pro Gly 355 360 365 Ser Cys Ile Asn Asn Trp His Arg ArgHis Gly Tyr Thr Ser Ser Leu 370 375 380 Glu Leu Pro Asp Asn Ile Leu AsnPhe Val Lys Lys His Pro Leu Met 385 390 395 400 Glu Glu Gln Val Gly ProArg Trp Ser Arg Pro Leu Leu Val Lys Lys 405 410 415 Gly Thr Asn Phe ThrHis Leu Val Ala Asp Arg Val Thr Gly Leu Asp 420 425 430 Gly Ala Thr TyrThr Val Leu Phe Ile Gly Thr Gly Asp Gly Trp Leu 435 440 445 Leu Lys AlaVal Ser Leu Gly Pro Trp Val His Leu Ile Glu Glu Leu 450 455 460 Gln LeuPhe Asp Gln Glu Pro Met Arg Ser Leu Val Leu Ser Gln Ser 465 470 475 480Lys Lys Leu Leu Phe Ala Gly Ser Arg Ser Gln Leu Val Gln Leu Pro 485 490495 Val Ala Asp Cys Met Lys Tyr Arg Ser Cys Ala Asp Cys Val Leu Ala 500505 510 Arg Asp Pro Tyr Cys Ala Trp Ser Val Asn Thr Ser Arg Cys Val Ala515 520 525 Val Gly Gly His Ser Gly Ser Leu Leu Ile Gln His Val Met ThrSer 530 535 540 Asp Thr Ser Gly Ile Cys Asn Leu Arg Gly Ser Lys Lys ValArg Pro 545 550 555 560 Thr Pro Lys Asn Ile Thr Val Val Ala Gly Thr AspLeu Val Leu Pro 565 570 575 Cys His Leu Ser Ser Asn Leu Ala His Ala ArgTrp Thr Phe Gly Gly 580 585 590 Arg Asp Leu Pro Ala Glu Gln Pro Gly SerPhe Leu Tyr Asp Ala Arg 595 600 605 Leu Gln Ala Leu Val Val Met Ala AlaGln Pro Arg His Ala Gly Ala 610 615 620 Tyr His Cys Phe Ser Glu Glu GlnGly Ala Arg Leu Ala Ala Glu Gly 625 630 635 640 Tyr Leu Val Ala Val ValAla Gly Pro Ser Val Thr Leu Glu Ala Arg 645 650 655 Ala Pro Leu Glu AsnLeu Gly Leu Val Trp Leu Ala Val Val Ala Leu 660 665 670 Gly Ala Val CysLeu Val Leu Leu Leu Leu Val Leu Ser Leu Arg Arg 675 680 685 Arg Leu ArgGlu Glu Leu Glu Lys Gly Ala Lys Ala Thr Glu Arg Thr 690 695 700 Leu ValTyr Pro Leu Glu Leu Pro Lys Glu Pro Thr Ser Pro Pro Phe 705 710 715 720Arg Pro Cys Pro Glu Pro Asp Glu Lys Leu Trp Asp Pro Val Gly Tyr 725 730735 Tyr Tyr Ser Asp Gly Ser Leu Lys Ile Val Pro Gly His Ala Arg Cys 740745 750 Gln Pro Gly Gly Gly Pro Pro Ser Pro Pro Pro Gly Ile Pro Gly Gln755 760 765 Pro Leu Pro Ser Pro Thr Arg Leu His Leu Gly Gly Gly Arg AsnSer 770 775 780 Asn Ala Asn Gly Tyr Val Arg Leu Gln Leu Gly Gly Glu AspArg Gly 785 790 795 800 Gly Leu Gly His Pro Leu Pro Glu Leu Ala Asp GluLeu Arg Arg Lys 805 810 815 Leu Gln Gln Arg Gln Pro Leu Pro Asp Ser AsnPro Glu Glu Ser Ser 820 825 830 Val 19 603 DNA Homo sapiens 19ttttttttaa atttatcttt aggtgcaata atgaagagtt ttcttctagt tgtcaatgcc 60ctggcattaa ccctgccttt tttgctagtg gaggttcaaa accagaaaca accagcatgc 120catgagaatg atgaaagacc attctatcag aaaacgttca catatgtccc aatgtattat 180gtgcaaaata gctatcttta ttatggaccc aatttgtaca aacgtagacc agctatagca 240ttaaataatc aatatgggct tcgcacatat tatgcaaccc aagctgtagt tagggcacat 300gcccaaattc ctcagcggca atacctgcca aatagccacc acactgtggt acgtcgccca 360aacctgcatc catcatttat tgcaatcccc ccaaagaaaa ttcaggataa aataatcatc 420cctaccatca ataccattgc tactgttgaa cctacaccag ctcctgccac tgaaccaacg 480gtggacagtg taatcactcc agaagctttt tcagagtcca tcatcacgag cacccctgag 540acaaccacag ttgcagttac tccacctacg gcataaaaac accaaggaaa tatcaaagaa 600cac 603 20 181 PRT Homo sapiens 20 Met Lys Ser Phe Leu Leu Val Val AsnAla Leu Ala Leu Thr Leu Pro 1 5 10 15 Phe Leu Leu Val Glu Val Gln AsnGln Lys Gln Pro Ala Cys His Glu 20 25 30 Asn Asp Glu Arg Pro Phe Tyr GlnLys Thr Phe Thr Tyr Val Pro Met 35 40 45 Tyr Tyr Val Gln Asn Ser Tyr LeuTyr Tyr Gly Pro Asn Leu Tyr Lys 50 55 60 Arg Arg Pro Ala Ile Ala Leu AsnAsn Gln Tyr Gly Leu Arg Thr Tyr 65 70 75 80 Tyr Ala Thr Gln Ala Val ValArg Ala His Ala Gln Ile Pro Gln Arg 85 90 95 Gln Tyr Leu Pro Asn Ser HisHis Thr Val Val Arg Arg Pro Asn Leu 100 105 110 His Pro Ser Phe Ile AlaIle Pro Pro Lys Lys Ile Gln Asp Lys Ile 115 120 125 Ile Ile Pro Thr IleAsn Thr Ile Ala Thr Val Glu Pro Thr Pro Ala 130 135 140 Pro Ala Thr GluPro Thr Val Asp Ser Val Ile Thr Pro Glu Ala Phe 145 150 155 160 Ser GluSer Ile Ile Thr Ser Thr Pro Glu Thr Thr Thr Val Ala Val 165 170 175 ThrPro Pro Thr Ala 180 21 1765 DNA Homo sapiens 21 aaagcctgcg agcgccagccgagatcgcat cccaacccat ggccgggtct cctagccgcg 60 ccgcgggccg gcgactgcagcttcccctgc tgtgcctctt cctccagggc gccactgccg 120 tcctctttgc tgtctttgtccgctacaacc acaaaaccga cgctgccctc tggcaccgga 180 gcaaccacag taacgcggacaatgaatttt actttcgcta cccaagtttc caggacgtgc 240 atgccatggt cttcgtgggctttgacttcc tcatggtctt cctgcagcgt tacggcttca 300 gcagcgtggg cttcaccttcctcctggccg cctttgccct gcagtggtcc acactggtcc 360 agggctttct ccactccttccacggtggcc acatccatgt tggcgtggag agcatgatca 420 atgctgactt ttgtgcgggggccgtgctca tctcctttgg tgccgtcctg ggcaagaccg 480 ggcctaccca gctgctgctcatggccctgc tggaggtggt gctgtttggc atcaatgagt 540 ttgtgctcct tcatctcctgggggtgagag tctggggagg gatttctagg gttatgtcta 600 gtaccatgct ggagaagagcaagcaccgcc agggctccgt ctaccattca gacctcttcg 660 ccatgattgg tgggaccatcttcctgtgga tcttctggcc tagcttcaat gctgcactca 720 cagcgctggg ggctgggcagcatcggacgg ccctcaacac atactactcc ctggctgcca 780 gcacccttgg cacctttgccttgtcagccc ttgtagggga agatgggagg cttgacatgg 840 tagtccacat ccaaaatgcagcgctggctg gaggggttgt ggtggggacc tcaagtgaaa 900 tgatgctgac accctttggggctctggcag ctggcttctt ggctgggact gtctccacgc 960 tggggtacaa gttcttcacgcccatccttg aatcaaaatt caaagtccaa gacacatgtg 1020 gagtccacaa cctccatgggatgccggggg tcctgggggc cctcctgggg gtccttgtgg 1080 ctggacttgc cacccatgaagcttacggag atgggctgga gagtgtgttt ccactcatag 1140 ccgagggcca gcgcagtgccacgtcacagg ccatgcacca gctcttcggg ctgtttgtca 1200 cactgatgtt tgcctctgtgggcgggggcc ttggaggtgg gctcctgctg aagctaccct 1260 ttctggactc cccccccgactcccagcact acgaggacca agttcactgg caggtggtgc 1320 ctggcgagca tgaggataaagcccagagac ctctgagggt ggaggaggca gacactcagg 1380 cctaacccac tgccagcccctgagaggaca cgctcctttt cgaagatgct gactggctgc 1440 tactaggaag ttctttttgagctcccattc ctccagctgc aagaagggag ccatgagcca 1500 gaaggaggcc cctttccacaggcagcgtct ccacagggag aggggcaaca ggaggctggg 1560 aaatggtggg gagtggggccgtaactgggt acaatagggg gaacctcacc agatgcccaa 1620 cccgactgcc ctaccagcctgcacatgggt agaagaggcc aaattgaggc acccaagtga 1680 tccactggcc ccacgtcacacagttacagt gaagcccaag ccaggcctgg ttgagggtga 1740 taaacgccac tgtctttaaggaaaa 1765 22 448 PRT Homo sapiens 22 Met Ala Gly Ser Pro Ser Arg AlaAla Gly Arg Arg Leu Gln Leu Pro 1 5 10 15 Leu Leu Cys Leu Phe Leu GlnGly Ala Thr Ala Val Leu Phe Ala Val 20 25 30 Phe Val Arg Tyr Asn His LysThr Asp Ala Ala Leu Trp His Arg Ser 35 40 45 Asn His Ser Asn Ala Asp AsnGlu Phe Tyr Phe Arg Tyr Pro Ser Phe 50 55 60 Gln Asp Val His Ala Met ValPhe Val Gly Phe Asp Phe Leu Met Val 65 70 75 80 Phe Leu Gln Arg Tyr GlyPhe Ser Ser Val Gly Phe Thr Phe Leu Leu 85 90 95 Ala Ala Phe Ala Leu GlnTrp Ser Thr Leu Val Gln Gly Phe Leu His 100 105 110 Ser Phe His Gly GlyHis Ile His Val Gly Val Glu Ser Met Ile Asn 115 120 125 Ala Asp Phe CysAla Gly Ala Val Leu Ile Ser Phe Gly Ala Val Leu 130 135 140 Gly Lys ThrGly Pro Thr Gln Leu Leu Leu Met Ala Leu Leu Glu Val 145 150 155 160 ValLeu Phe Gly Ile Asn Glu Phe Val Leu Leu His Leu Leu Gly Val 165 170 175Arg Val Trp Gly Gly Ile Ser Arg Val Met Ser Ser Thr Met Leu Glu 180 185190 Lys Ser Lys His Arg Gln Gly Ser Val Tyr His Ser Asp Leu Phe Ala 195200 205 Met Ile Gly Gly Thr Ile Phe Leu Trp Ile Phe Trp Pro Ser Phe Asn210 215 220 Ala Ala Leu Thr Ala Leu Gly Ala Gly Gln His Arg Thr Ala LeuAsn 225 230 235 240 Thr Tyr Tyr Ser Leu Ala Ala Ser Thr Leu Gly Thr PheAla Leu Ser 245 250 255 Ala Leu Val Gly Glu Asp Gly Arg Leu Asp Met ValVal His Ile Gln 260 265 270 Asn Ala Ala Leu Ala Gly Gly Val Val Val GlyThr Ser Ser Glu Met 275 280 285 Met Leu Thr Pro Phe Gly Ala Leu Ala AlaGly Phe Leu Ala Gly Thr 290 295 300 Val Ser Thr Leu Gly Tyr Lys Phe PheThr Pro Ile Leu Glu Ser Lys 305 310 315 320 Phe Lys Val Gln Asp Thr CysGly Val His Asn Leu His Gly Met Pro 325 330 335 Gly Val Leu Gly Ala LeuLeu Gly Val Leu Val Ala Gly Leu Ala Thr 340 345 350 His Glu Ala Tyr GlyAsp Gly Leu Glu Ser Val Phe Pro Leu Ile Ala 355 360 365 Glu Gly Gln ArgSer Ala Thr Ser Gln Ala Met His Gln Leu Phe Gly 370 375 380 Leu Phe ValThr Leu Met Phe Ala Ser Val Gly Gly Gly Leu Gly Gly 385 390 395 400 GlyLeu Leu Leu Lys Leu Pro Phe Leu Asp Ser Pro Pro Asp Ser Gln 405 410 415His Tyr Glu Asp Gln Val His Trp Gln Val Val Pro Gly Glu His Glu 420 425430 Asp Lys Ala Gln Arg Pro Leu Arg Val Glu Glu Ala Asp Thr Gln Ala 435440 445 23 1399 DNA Homo sapiens 23 tgttttactt gaaatgctac aaaccaacactctttttatc ctaaaacagg agtctgtgtt 60 ttatgtttcc ctttggtttc ctcagactcagattagtcct aaagaagggt ggcaggtgta 120 cagctcagct caggatcctg atgggcggtgcatttgcaca gttgttgctc cagaacaaaa 180 cctgtgttcc cgggatgcca aaagcaggcaacttcgccaa ctactggaaa aggtacagaa 240 catgtcccag tctattgaag tcttaaacttgagaactcag agagatttcc aatatgtttt 300 aaaaatggaa acccaaatga aagggctgaaggcaaaattt cggcagattg aagatgatcg 360 aaagacactt atgaccaagc attttcagcaggagttgaaa gagaaaatgg acgagctcct 420 gcctttgatc cccgtgctgg aacagtgcaaaacagatgct aagttcatca cccagttcaa 480 ggaggaaata aggaatctgt ctgctgtcctcactggtatt caggaggaaa ttggtgccta 540 tgactacgag gaactacacc aaagagtgctgagcttggaa acaagacttc gtgactgcat 600 gaaaaagcta tgtggcaaac tgatgaaaatcacaggccca gttacagtca agacatctgg 660 aacccgattt ggtgcttgga tgacagaccctttagcatct gagaaaaaca acagagtatg 720 gtacatggac agttatacta acaataaaattgttcgtgaa tacaaatcaa ttgcagactt 780 tgtcagtggg gctgaatcaa ggacatacaaccttcctttc aagtgggcag gaactaacca 840 tgttgtctac aatggctcac tctattttaacaagtatcag agtaatatca tcatcaaata 900 cagctttgat atggggagag tgcttgcccaacgaagcctg gagtatgctg gttttcataa 960 tgtttacccc tacacatggg gtggattctctgacatcgac ctaatggctg atgaaatcgg 1020 gctgtgggct gtgtatgcaa ctaaccagaatgcaggcaat attgtcatca gccaacttaa 1080 ccaagatacc ttggaggtga tgaagagctggagcactggc taccccaaga gaagtgcagg 1140 ggaatctttc atgatctgtg ggacactgtatgtcaccaac tcccacttaa ctggagccaa 1200 ggtgtattat tcctattcca ccaaaacctccacatatgag tacacagaca ttcccttcca 1260 taaccaatac tttcacatat ccatgcttgactacaatgca agagatcgag ctctctatgc 1320 ctggaacaat ggccaccagg tgctgttcaatgtcaccctt ttccatatca tcaagacaga 1380 ggatgacaca taggcaaat 1399 24 459PRT Homo sapiens 24 Met Leu Gln Thr Asn Thr Leu Phe Ile Leu Lys Gln GluSer Val Phe 1 5 10 15 Tyr Val Ser Leu Trp Phe Pro Gln Thr Gln Ile SerPro Lys Glu Gly 20 25 30 Trp Gln Val Tyr Ser Ser Ala Gln Asp Pro Asp GlyArg Cys Ile Cys 35 40 45 Thr Val Val Ala Pro Glu Gln Asn Leu Cys Ser ArgAsp Ala Lys Ser 50 55 60 Arg Gln Leu Arg Gln Leu Leu Glu Lys Val Gln AsnMet Ser Gln Ser 65 70 75 80 Ile Glu Val Leu Asn Leu Arg Thr Gln Arg AspPhe Gln Tyr Val Leu 85 90 95 Lys Met Glu Thr Gln Met Lys Gly Leu Lys AlaLys Phe Arg Gln Ile 100 105 110 Glu Asp Asp Arg Lys Thr Leu Met Thr LysHis Phe Gln Gln Glu Leu 115 120 125 Lys Glu Lys Met Asp Glu Leu Leu ProLeu Ile Pro Val Leu Glu Gln 130 135 140 Cys Lys Thr Asp Ala Lys Phe IleThr Gln Phe Lys Glu Glu Ile Arg 145 150 155 160 Asn Leu Ser Ala Val LeuThr Gly Ile Gln Glu Glu Ile Gly Ala Tyr 165 170 175 Asp Tyr Glu Glu LeuHis Gln Arg Val Leu Ser Leu Glu Thr Arg Leu 180 185 190 Arg Asp Cys MetLys Lys Leu Cys Gly Lys Leu Met Lys Ile Thr Gly 195 200 205 Pro Val ThrVal Lys Thr Ser Gly Thr Arg Phe Gly Ala Trp Met Thr 210 215 220 Asp ProLeu Ala Ser Glu Lys Asn Asn Arg Val Trp Tyr Met Asp Ser 225 230 235 240Tyr Thr Asn Asn Lys Ile Val Arg Glu Tyr Lys Ser Ile Ala Asp Phe 245 250255 Val Ser Gly Ala Glu Ser Arg Thr Tyr Asn Leu Pro Phe Lys Trp Ala 260265 270 Gly Thr Asn His Val Val Tyr Asn Gly Ser Leu Tyr Phe Asn Lys Tyr275 280 285 Gln Ser Asn Ile Ile Ile Lys Tyr Ser Phe Asp Met Gly Arg ValLeu 290 295 300 Ala Gln Arg Ser Leu Glu Tyr Ala Gly Phe His Asn Val TyrPro Tyr 305 310 315 320 Thr Trp Gly Gly Phe Ser Asp Ile Asp Leu Met AlaAsp Glu Ile Gly 325 330 335 Leu Trp Ala Val Tyr Ala Thr Asn Gln Asn AlaGly Asn Ile Val Ile 340 345 350 Ser Gln Leu Asn Gln Asp Thr Leu Glu ValMet Lys Ser Trp Ser Thr 355 360 365 Gly Tyr Pro Lys Arg Ser Ala Gly GluSer Phe Met Ile Cys Gly Thr 370 375 380 Leu Tyr Val Thr Asn Ser His LeuThr Gly Ala Lys Val Tyr Tyr Ser 385 390 395 400 Tyr Ser Thr Lys Thr SerThr Tyr Glu Tyr Thr Asp Ile Pro Phe His 405 410 415 Asn Gln Tyr Phe HisIle Ser Met Leu Asp Tyr Asn Ala Arg Asp Arg 420 425 430 Ala Leu Tyr AlaTrp Asn Asn Gly His Gln Val Leu Phe Asn Val Thr 435 440 445 Leu Phe HisIle Ile Lys Thr Glu Asp Asp Thr 450 455 25 2524 PRT Xenopus laevis 25Met Asp Arg Ile Gly Leu Ala Val Leu Leu Cys Ser Leu Pro Val Leu 1 5 1015 Thr Gln Gly Leu Arg Pro Cys Thr Gln Thr Ala Glu Met Cys Leu Asn 20 2530 Gly Gly Arg Cys Glu Met Thr Pro Gly Gly Thr Gly Val Cys Leu Cys 35 4045 Gly Asn Leu Tyr Phe Gly Glu Arg Cys Gln Phe Pro Asn Pro Cys Thr 50 5560 Ile Lys Asn Gln Cys Met Asn Phe Gly Thr Cys Glu Pro Val Leu Gln 65 7075 80 Gly Asn Ala Ile Asp Phe Ile Cys His Cys Pro Val Gly Phe Thr Asp 8590 95 Lys Val Cys Leu Thr Pro Val Asp Asn Ala Cys Val Asn Asn Pro Cys100 105 110 Arg Asn Gly Gly Thr Cys Glu Leu Leu Asn Ser Val Thr Glu TyrLys 115 120 125 Cys Arg Cys Pro Pro Gly Trp Thr Gly Asp Ser Cys Gln GlnAla Asp 130 135 140 Pro Cys Ala Ser Asn Pro Cys Ala Asn Gly Gly Lys CysLeu Pro Phe 145 150 155 160 Glu Ile Gln Tyr Ile Cys Lys Cys Pro Pro GlyPhe His Gly Ala Thr 165 170 175 Cys Lys Gln Asp Ile Asn Glu Cys Ser GlnAsn Pro Cys Lys Asn Gly 180 185 190 Gly Gln Cys Ile Asn Glu Phe Gly SerTyr Arg Cys Thr Cys Gln Asn 195 200 205 Arg Phe Thr Gly Arg Asn Cys AspGlu Pro Tyr Val Pro Cys Asn Pro 210 215 220 Ser Pro Cys Leu Asn Gly GlyThr Cys Arg Gln Thr Asp Asp Thr Ser 225 230 235 240 Tyr Asp Cys Thr CysLeu Pro Gly Phe Ser Gly Gln Asn Cys Glu Glu 245 250 255 Asn Ile Asp AspCys Pro Ser Asn Asn Cys Arg Asn Gly Gly Thr Cys 260 265 270 Val Asp GlyVal Asn Thr Tyr Asn Cys Gln Cys Pro Pro Asp Trp Thr 275 280 285 Gly GlnTyr Cys Thr Glu Asp Val Asp Glu Cys Gln Leu Met Pro Asn 290 295 300 AlaCys Gln Asn Gly Gly Thr Cys His Asn Thr Tyr Gly Gly Tyr Asn 305 310 315320 Cys Val Cys Val Asn Gly Trp Thr Gly Glu Asp Cys Ser Glu Asn Ile 325330 335 Asp Asp Cys Ala Asn Ala Ala Cys His Ser Gly Ala Thr Cys His Asp340 345 350 Arg Val Ala Ser Phe Tyr Cys Glu Cys Pro His Gly Arg Thr GlyLeu 355 360 365 Leu Cys His Leu Asp Asn Ala Cys Ile Ser Asn Pro Cys AsnGlu Gly 370 375 380 Ser Asn Cys Asp Thr Asn Pro Val Asn Gly Lys Ala IleCys Thr Cys 385 390 395 400 Pro Pro Gly Tyr Thr Gly Pro Ala Cys Asn AsnAsp Val Asp Glu Cys 405 410 415 Ser Leu Gly Ala Asn Pro Cys Glu Arg GlyGly Arg Cys Thr Asn Thr 420 425 430 Leu Gly Ser Phe Gln Cys Asn Cys ProGln Gly Tyr Ala Gly Pro Arg 435 440 445 Cys Glu Ile Asp Val Asn Glu CysLeu Ser Asn Pro Cys Gln Asn Asp 450 455 460 Ser Thr Cys Leu Asp Gln IleGly Glu Phe Gln Cys Ile Cys Met Pro 465 470 475 480 Gly Tyr Glu Gly LeuTyr Cys Glu Thr Asn Ile Asp Glu Cys Ala Ser 485 490 495 Asn Pro Cys LeuHis Asn Gly Lys Cys Ile Asp Lys Ile Asn Glu Phe 500 505 510 Arg Cys AspCys Pro Thr Gly Phe Ser Gly Asn Leu Cys Gln His Asp 515 520 525 Phe AspGlu Cys Thr Ser Thr Pro Cys Lys Asn Gly Ala Lys Cys Leu 530 535 540 AspGly Pro Asn Ser Tyr Thr Cys Gln Cys Thr Glu Gly Phe Thr Gly 545 550 555560 Arg His Cys Glu Gln Asp Ile Asn Glu Cys Ile Pro Asp Pro Cys His 565570 575 Tyr Gly Thr Cys Lys Asp Gly Ile Ala Thr Phe Thr Cys Leu Cys Arg580 585 590 Pro Gly Tyr Thr Gly Arg Leu Cys Asp Asn Asp Ile Asn Glu CysLeu 595 600 605 Ser Lys Pro Cys Leu Asn Gly Gly Gln Cys Thr Asp Arg GluAsn Gly 610 615 620 Tyr Ile Cys Thr Cys Pro Lys Gly Thr Thr Gly Val AsnCys Glu Thr 625 630 635 640 Lys Ile Asp Asp Cys Ala Ser Asn Leu Cys AspAsn Gly Lys Cys Ile 645 650 655 Asp Lys Ile Asp Gly Tyr Glu Cys Thr CysGlu Pro Gly Tyr Thr Gly 660 665 670 Lys Leu Cys Asn Ile Asn Ile Asn GluCys Asp Ser Asn Pro Cys Arg 675 680 685 Asn Gly Gly Thr Cys Lys Asp GlnIle Asn Gly Phe Thr Cys Val Cys 690 695 700 Pro Asp Gly Tyr His Asp HisMet Cys Leu Ser Glu Val Asn Glu Cys 705 710 715 720 Asn Ser Asn Pro CysIle His Gly Ala Cys His Asp Gly Val Asn Gly 725 730 735 Tyr Lys Cys AspCys Glu Ala Gly Trp Ser Gly Ser Asn Cys Asp Ile 740 745 750 Asn Asn AsnGlu Cys Glu Ser Asn Pro Cys Met Asn Gly Gly Thr Cys 755 760 765 Lys AspMet Thr Gly Ala Tyr Ile Cys Thr Cys Lys Ala Gly Phe Ser 770 775 780 GlyPro Asn Cys Gln Thr Asn Ile Asn Glu Cys Ser Ser Asn Pro Cys 785 790 795800 Leu Asn His Gly Thr Cys Ile Asp Asp Val Ala Gly Tyr Lys Cys Asn 805810 815 Cys Met Leu Pro Tyr Thr Gly Ala Ile Cys Glu Ala Val Leu Ala Pro820 825 830 Cys Ala Gly Ser Pro Cys Lys Asn Gly Gly Arg Cys Lys Glu SerGlu 835 840 845 Asp Phe Glu Thr Phe Ser Cys Glu Cys Pro Pro Gly Trp GlnGly Gln 850 855 860 Thr Cys Glu Ile Asp Met Asn Glu Cys Val Asn Arg ProCys Arg Asn 865 870 875 880 Gly Ala Thr Cys Gln Asn Thr Asn Gly Ser TyrLys Cys Asn Cys Lys 885 890 895 Pro Gly Tyr Thr Gly Arg Asn Cys Glu MetAsp Ile Asp Asp Cys Gln 900 905 910 Pro Asn Pro Cys His Asn Gly Gly SerCys Ser Asp Gly Ile Asn Met 915 920 925 Phe Phe Cys Asn Cys Pro Ala GlyPhe Arg Gly Pro Lys Cys Glu Glu 930 935 940 Asp Ile Asn Glu Cys Ala SerAsn Pro Cys Lys Asn Gly Ala Asn Cys 945 950 955 960 Thr Asp Cys Val AsnSer Tyr Thr Cys Thr Cys Gln Pro Gly Phe Ser 965 970 975 Gly Ile His CysGlu Ser Asn Thr Pro Asp Cys Thr Glu Ser Ser Cys 980 985 990 Phe Asn GlyGly Thr Cys Ile Asp Gly Ile Asn Thr Phe Thr Cys Gln 995 1000 1005 CysPro Pro Gly Phe Thr Gly Ser Tyr Cys Gln His Asp Ile Asn Glu 1010 10151020 Cys Asp Ser Lys Pro Cys Leu Asn Gly Gly Thr Cys Gln Asp Ser Tyr1025 1030 1035 1040 Gly Thr Tyr Lys Cys Thr Cys Pro Gln Gly Tyr Thr GlyLeu Asn Cys 1045 1050 1055 Gln Asn Leu Val Arg Trp Cys Asp Ser Ser ProCys Lys Asn Gly Gly 1060 1065 1070 Lys Cys Trp Gln Thr Asn Asn Phe TyrArg Cys Glu Cys Lys Ser Gly 1075 1080 1085 Trp Thr Gly Val Tyr Cys AspVal Pro Ser Val Ser Cys Glu Val Ala 1090 1095 1100 Ala Lys Gln Gln GlyVal Asp Ile Val His Leu Cys Arg Asn Ser Gly 1105 1110 1115 1120 Met CysVal Asp Thr Gly Asn Thr His Phe Cys Arg Cys Gln Ala Gly 1125 1130 1135Tyr Thr Gly Ser Tyr Cys Glu Glu Gln Val Asp Glu Cys Ser Pro Asn 11401145 1150 Pro Cys Gln Asn Gly Ala Thr Cys Thr Asp Tyr Leu Gly Gly TyrSer 1155 1160 1165 Cys Glu Cys Val Ala Gly Tyr His Gly Val Asn Cys SerGlu Glu Ile 1170 1175 1180 Asn Glu Cys Leu Ser His Pro Cys Gln Asn GlyGly Thr Cys Ile Asp 1185 1190 1195 1200 Leu Ile Asn Thr Tyr Lys Cys SerCys Pro Arg Gly Thr Gln Gly Val 1205 1210 1215 His Cys Glu Ile Asn ValAsp Asp Cys Thr Pro Phe Tyr Asp Ser Phe 1220 1225 1230 Thr Leu Glu ProLys Cys Phe Asn Asn Gly Lys Cys Ile Asp Arg Val 1235 1240 1245 Gly GlyTyr Asn Cys Ile Cys Pro Pro Gly Phe Val Gly Glu Arg Cys 1250 1255 1260Glu Gly Asp Val Asn Glu Cys Leu Ser Asn Pro Cys Asp Ser Arg Gly 12651270 1275 1280 Thr Gln Asn Cys Ile Gln Leu Val Asn Asp Tyr Arg Cys GluCys Arg 1285 1290 1295 Gln Gly Phe Thr Gly Arg Arg Cys Glu Ser Val ValAsp Gly Cys Lys 1300 1305 1310 Gly Met Pro Cys Arg Asn Gly Gly Thr CysAla Val Ala Ser Asn Thr 1315 1320 1325 Glu Arg Gly Phe Ile Cys Lys CysPro Pro Gly Phe Asp Gly Ala Thr 1330 1335 1340 Cys Glu Tyr Asp Ser ArgThr Cys Ser Asn Leu Arg Cys Gln Asn Gly 1345 1350 1355 1360 Gly Thr CysIle Ser Val Leu Thr Ser Ser Lys Cys Val Cys Ser Glu 1365 1370 1375 GlyTyr Thr Gly Ala Thr Cys Gln Tyr Pro Val Ile Ser Pro Cys Ala 1380 13851390 Ser His Pro Cys Tyr Asn Gly Gly Thr Cys Gln Phe Phe Ala Glu Glu1395 1400 1405 Pro Phe Phe Gln Cys Phe Cys Pro Lys Asn Phe Asn Gly LeuPhe Cys 1410 1415 1420 His Ile Leu Asp Tyr Glu Phe Pro Gly Gly Leu GlyLys Asn Ile Thr 1425 1430 1435 1440 Pro Pro Asp Asn Asp Asp Ile Cys GluAsn Glu Gln Cys Ser Glu Leu 1445 1450 1455 Ala Asp Asn Lys Val Cys AsnAla Asn Cys Asn Asn His Ala Cys Gly 1460 1465 1470 Trp Asp Gly Gly AspCys Ser Leu Asn Phe Asn Asp Pro Trp Lys Asn 1475 1480 1485 Cys Thr GlnSer Leu Gln Cys Trp Lys Tyr Phe Asn Asp Gly Lys Cys 1490 1495 1500 AspSer Gln Cys Asn Asn Thr Gly Cys Leu Tyr Asp Gly Phe Asp Cys 1505 15101515 1520 Gln Lys Val Glu Val Gln Cys Asn Pro Leu Tyr Asp Gln Tyr CysLys 1525 1530 1535 Asp His Phe Gln Asp Gly His Cys Asp Gln Gly Cys AsnAsn Ala Glu 1540 1545 1550 Cys Glu Trp Asp Gly Leu Asp Cys Ala Asn MetPro Glu Asn Leu Ala 1555 1560 1565 Glu Gly Thr Leu Val Leu Val Val LeuMet Pro Pro Glu Arg Leu Lys 1570 1575 1580 Asn Asn Ser Val Asn Phe LeuArg Glu Leu Ser Arg Val Leu His Thr 1585 1590 1595 1600 Asn Val Val PheLys Lys Asp Ser Lys Gly Glu Tyr Lys Ile Tyr Pro 1605 1610 1615 Tyr TyrGly Asn Glu Glu Glu Leu Lys Lys His His Ile Lys Arg Ser 1620 1625 1630Thr Asp Tyr Trp Ser Asp Ala Pro Ser Ala Ile Phe Ser Thr Met Lys 16351640 1645 Glu Ser Ile Leu Leu Gly Arg His Arg Arg Glu Leu Asp Glu MetGlu 1650 1655 1660 Val Arg Gly Ser Ile Val Tyr Leu Glu Ile Asp Asn ArgGln Cys Tyr 1665 1670 1675 1680 Lys Ser Ser Ser Gln Cys Phe Asn Ser AlaThr Asp Val Ala Ala Phe 1685 1690 1695 Leu Gly Ala Leu Ala Ser Leu GlySer Leu Asp Thr Leu Ser Tyr Lys 1700 1705 1710 Ile Glu Ala Val Lys SerGlu Asn Met Glu Thr Pro Lys Pro Ser Thr 1715 1720 1725 Leu Tyr Pro MetLeu Ser Met Leu Val Ile Pro Leu Leu Ile Ile Phe 1730 1735 1740 Val PheMet Met Val Ile Val Asn Lys Lys Arg Arg Arg Glu His Asp 1745 1750 17551760 Ser Phe Gly Ser Pro Thr Ala Leu Phe Gln Lys Asn Pro Ala Lys Arg1765 1770 1775 Asn Gly Glu Thr Pro Trp Glu Asp Ser Val Gly Leu Lys ProIle Lys 1780 1785 1790 Asn Met Thr Asp Gly Ser Phe Met Asp Asp Asn GlnAsn Glu Trp Gly 1795 1800 1805 Asp Glu Glu Thr Leu Glu Asn Lys Arg PheArg Phe Glu Glu Gln Val 1810 1815 1820 Ile Leu Pro Glu Leu Val Asp AspLys Thr Asp Pro Arg Gln Trp Thr 1825 1830 1835 1840 Arg Gln His Leu AspAla Ala Asp Leu Arg Ile Ser Ser Met Ala Pro 1845 1850 1855 Thr Pro ProGln Gly Glu Ile Glu Ala Asp Cys Met Asp Val Asn Val 1860 1865 1870 ArgGly Pro Asp Gly Phe Thr Pro Leu Met Ile Ala Ser Cys Ser Gly 1875 18801885 Gly Gly Leu Glu Thr Gly Asn Ser Glu Glu Glu Glu Asp Ala Ser Ala1890 1895 1900 Asn Met Ile Ser Asp Phe Ile Gly Gln Gly Ala Gln Leu HisAsn Gln 1905 1910 1915 1920 Thr Asp Arg Thr Gly Glu Thr Ala Leu His LeuAla Ala Arg Tyr Ala 1925 1930 1935 Arg Ala Asp Ala Ala Lys Arg Leu LeuGlu Ser Ser Ala Asp Ala Asn 1940 1945 1950 Val Gln Asp Asn Met Gly ArgThr Pro Leu His Ala Ala Val Ala Ala 1955 1960 1965 Asp Ala Gln Gly ValPhe Gln Ile Leu Ile Arg Asn Arg Ala Thr Asp 1970 1975 1980 Leu Asp AlaArg Met Phe Asp Gly Thr Thr Pro Leu Ile Leu Ala Ala 1985 1990 1995 2000Arg Leu Ala Val Glu Gly Met Val Glu Glu Leu Ile Asn Ala His Ala 20052010 2015 Asp Val Asn Ala Val Asp Glu Phe Gly Lys Ser Ala Leu His TrpAla 2020 2025 2030 Ala Ala Val Asn Asn Val Asp Ala Ala Ala Val Leu LeuLys Asn Ser 2035 2040 2045 Ala Asn Lys Asp Met Gln Asn Asn Lys Glu GluThr Ser Leu Phe Leu 2050 2055 2060 Ala Ala Arg Glu Gly Ser Tyr Glu ThrAla Lys Val Leu Leu Asp His 2065 2070 2075 2080 Tyr Ala Asn Arg Asp IleThr Asp His Met Asp Arg Leu Pro Arg Asp 2085 2090 2095 Ile Ala Gln GluArg Met His His Asp Ile Val His Leu Leu Asp Glu 2100 2105 2110 Tyr AsnLeu Val Lys Ser Pro Thr Leu His Asn Gly Pro Leu Gly Ala 2115 2120 2125Thr Thr Leu Ser Pro Pro Ile Cys Ser Pro Asn Gly Tyr Met Gly Asn 21302135 2140 Met Lys Pro Ser Val Gln Ser Lys Lys Ala Arg Lys Pro Ser IleLys 2145 2150 2155 2160 Gly Asn Gly Cys Lys Glu Ala Lys Glu Leu Lys AlaArg Arg Lys Lys 2165 2170 2175 Ser Gln Asp Gly Lys Thr Thr Leu Leu AspSer Gly Ser Ser Gly Val 2180 2185 2190 Leu Ser Pro Val Asp Ser Leu GluSer Thr His Gly Tyr Leu Ser Asp 2195 2200 2205 Val Ser Ser Pro Pro LeuMet Thr Ser Pro Phe Gln Gln Ser Pro Ser 2210 2215 2220 Met Pro Leu AsnHis Leu Thr Ser Met Pro Glu Ser Gln Leu Gly Met 2225 2230 2235 2240 AsnHis Ile Asn Met Ala Thr Lys Gln Glu Met Ala Ala Gly Ser Asn 2245 22502255 Arg Met Ala Phe Asp Ala Met Val Pro Arg Leu Thr His Leu Asn Ala2260 2265 2270 Ser Ser Pro Asn Thr Ile Met Ser Asn Gly Ser Met His PheThr Val 2275 2280 2285 Gly Gly Ala Pro Thr Met Asn Ser Gln Cys Asp TrpLeu Ala Arg Leu 2290 2295 2300 Gln Asn Gly Met Val Gln Asn Gln Tyr AspPro Ile Arg Asn Gly Ile 2305 2310 2315 2320 Gln Gln Gly Asn Ala Gln GlnAla Gln Ala Leu Gln His Gly Leu Met 2325 2330 2335 Thr Ser Leu His AsnGly Leu Pro Ala Thr Thr Leu Ser Gln Met Met 2340 2345 2350 Thr Tyr GlnAla Met Pro Asn Thr Arg Leu Ala Asn Gln Pro His Leu 2355 2360 2365 MetGln Ala Gln Gln Met Gln Gln Gln Gln Asn Leu Gln Leu His Gln 2370 23752380 Ser Met Gln Gln Gln His His Asn Ser Ser Thr Thr Ser Thr His Ile2385 2390 2395 2400 Asn Ser Pro Phe Cys Ser Ser Asp Ile Ser Gln Thr AspLeu Gln Gln 2405 2410 2415 Met Ser Ser Asn Asn Ile His Ser Val Met ProGln Asp Thr Gln Ile 2420 2425 2430 Phe Ala Ala Ser Leu Pro Ser Asn LeuThr Gln Ser Met Thr Thr Ala 2435 2440 2445 Gln Phe Leu Thr Pro Pro SerGln His Ser Tyr Ser Ser Pro Met Asp 2450 2455 2460 Asn Thr Pro Ser HisGln Leu Gln Val Pro Asp His Pro Phe Leu Thr 2465 2470 2475 2480 Pro SerPro Glu Ser Pro Asp Gln Trp Ser Ser Ser Ser Pro His Ser 2485 2490 2495Asn Met Ser Asp Trp Ser Glu Gly Ile Ser Ser Pro Pro Thr Ser Met 25002505 2510 Gln Pro Gln Arg Thr His Ile Pro Glu Ala Phe Lys 2515 2520 262317 PRT Drosophila melanogaster VARIANT (440) Wherein Xaa represents O.26 Met Gly Leu Gly Ala Arg Gly Arg Arg Arg Arg Arg Arg Leu Met Ala 1 510 15 Leu Pro Pro Pro Pro Pro Pro Met Arg Ala Leu Pro Leu Leu Leu Leu 2025 30 Leu Ala Gly Leu Gly Ala Ala Ala Pro Pro Cys Leu Asp Gly Ser Pro 3540 45 Cys Ala Asn Gly Gly Arg Cys Thr His Gln Gln Pro Ser Leu Glu Ala 5055 60 Ala Cys Leu Cys Leu Pro Gly Trp Val Gly Glu Arg Cys Gln Leu Glu 6570 75 80 Asp Pro Cys His Ser Gly Pro Cys Ala Gly Arg Gly Val Cys Gln Ser85 90 95 Ser Val Val Ala Gly Thr Ala Arg Phe Ser Cys Arg Cys Leu Arg Gly100 105 110 Phe Gln Gly Pro Asp Cys Ser Gln Pro Asp Pro Cys Val Ser ArgPro 115 120 125 Cys Val His Gly Ala Pro Cys Ser Val Gly Pro Asp Gly ArgPhe Ala 130 135 140 Cys Ala Cys Pro Pro Gly Tyr Gln Gly Gln Ser Cys GlnSer Asp Ile 145 150 155 160 Asp Glu Cys Arg Ser Gly Thr Thr Cys Arg HisGly Gly Thr Cys Leu 165 170 175 Asn Thr Pro Gly Ser Phe Arg Cys Gln CysPro Leu Gly Tyr Thr Gly 180 185 190 Leu Leu Cys Glu Asn Pro Val Val ProCys Ala Pro Ser Pro Cys Arg 195 200 205 Asn Gly Gly Thr Cys Arg Gln SerSer Asp Val Thr Tyr Asp Cys Ala 210 215 220 Cys Leu Pro Gly Phe Glu GlyGln Asn Cys Glu Val Asn Val Asp Asp 225 230 235 240 Cys Pro Gly His ArgCys Leu Asn Gly Gly Thr Cys Val Asp Gly Val 245 250 255 Asn Thr Tyr AsnCys Gln Cys Pro Pro Glu Trp Thr Gly Gln Phe Cys 260 265 270 Thr Glu AspVal Asp Glu Cys Gln Leu Gln Pro Asn Ala Cys His Asn 275 280 285 Gly GlyThr Cys Phe Asn Leu Leu Gly Gly His Ser Cys Val Cys Val 290 295 300 AsnGly Trp Thr Gly Glu Ser Cys Ser Gln Asn Ile Asp Asp Cys Ala 305 310 315320 Thr Ala Val Cys Phe His Gly Ala Thr Cys His Asp Arg Val Ala Ser 325330 335 Phe Tyr Cys Ala Cys Pro Met Gly Lys Thr Gly Leu Leu Cys His Leu340 345 350 Asp Asp Ala Cys Val Ser Asn Pro Cys His Glu Asp Ala Ile CysAsp 355 360 365 Thr Asn Pro Val Ser Gly Arg Ala Ile Cys Thr Cys Pro ProGly Phe 370 375 380 Thr Gly Gly Ala Cys Asp Gln Asp Val Asp Glu Cys SerIle Gly Ala 385 390 395 400 Asn Pro Cys Glu His Leu Gly Arg Cys Val AsnThr Gln Gly Ser Phe 405 410 415 Leu Cys Gln Cys Gly Arg Gly Tyr Thr GlyPro Arg Cys Glu Thr Asp 420 425 430 Val Asn Glu Cys Leu Ser Met Xaa LeuAsn Gln Ala Thr Cys Leu Asp 435 440 445 Arg Ile Gly Gln Phe Thr Cys IleCys Met Ala Gly Phe Thr Gly Thr 450 455 460 Tyr Cys Glu Val Asp Ile AspGlu Cys Gln Ser Ser Pro Cys Val Asn 465 470 475 480 Gly Gly Val Cys LysAsp Arg Val Asn Gly Phe Ser Cys Thr Cys Pro 485 490 495 Ser Gly Phe SerGly Ser Met Cys Gln Leu Asp Val Asp Glu Cys Ala 500 505 510 Ser Thr ProCys Arg Asn Gly Ala Lys Cys Val Asp Gln Pro Asp Gly 515 520 525 Tyr GluCys Arg Cys Ala Glu Gly Phe Glu Gly Thr Leu Cys Glu Arg 530 535 540 AsnVal Asp Asp Cys Ser Pro Asp Pro Cys His His Gly Arg Cys Val 545 550 555560 Asp Gly Ile Ala Ser Phe Ser Cys Ala Cys Ala Pro Gly Tyr Thr Gly 565570 575 Ile Arg Cys Glu Ser Gln Val Asp Glu Cys Arg Ser Gln Pro Cys Arg580 585 590 Tyr Gly Gly Lys Cys Leu Asp Leu Val Asp Lys Tyr Leu Cys ArgCys 595 600 605 Pro Pro Gly Thr Thr Gly Val Asn Cys Glu Val Asn Ile AspAsp Cys 610 615 620 Ala Ser Asn Pro Cys Thr Phe Gly Val Cys Arg Asp GlyIle Asn Arg 625 630 635 640 Tyr Asp Cys Val Cys Gln Pro Gly Phe Thr GlyPro Leu Cys Asn Val 645 650 655 Glu Ile Asn Glu Cys Ala Ser Ser Pro CysGly Glu Gly Gly Ser Cys 660 665 670 Val Asp Gly Glu Asn Gly Phe His CysLeu Cys Pro Pro Gly Ser Leu 675 680 685 Pro Pro Leu Cys Leu Pro Ala AsnHis Pro Cys Ala His Lys Pro Cys 690 695 700 Ser His Gly Val Cys His AspAla Pro Gly Gly Phe Arg Cys Val Cys 705 710 715 720 Glu Pro Gly Trp SerGly Pro Arg Cys Ser Gln Ser Leu Ala Pro Asp 725 730 735 Ala Cys Glu SerGln Pro Cys Gln Ala Gly Gly Thr Cys Thr Ser Asp 740 745 750 Gly Ile GlyPhe Arg Cys Thr Cys Ala Pro Gly Phe Gln Gly His Gln 755 760 765 Cys GluVal Leu Ser Pro Cys Thr Pro Ser Leu Cys Glu His Gly Gly 770 775 780 HisCys Glu Ser Asp Pro Asp Arg Leu Thr Val Cys Ser Cys Pro Pro 785 790 795800 Gly Trp Gln Gly Pro Arg Cys Gln Gln Asp Val Asp Glu Cys Ala Gly 805810 815 Ala Ser Pro Cys Gly Pro His Gly Thr Cys Thr Asn Leu Pro Gly Asn820 825 830 Phe Arg Cys Ile Cys His Arg Gly Tyr Thr Gly Pro Phe Cys AspGln 835 840 845 Asp Ile Asp Asp Cys Asp Pro Asn Pro Cys Leu His Gly GlySer Cys 850 855 860 Gln Asp Gly Val Gly Ser Phe Ser Cys Ser Cys Leu AspGly Phe Ala 865 870 875 880 Gly Pro Arg Cys Ala Arg Asp Val Asp Glu CysLeu Ser Ser Pro Cys 885 890 895 Gly Pro Gly Thr Cys Thr Asp His Val AlaSer Phe Thr Cys Ala Cys 900 905 910 Pro Pro Gly Tyr Gly Gly Phe His CysGlu Ile Asp Leu Pro Asp Cys 915 920 925 Ser Pro Ser Ser Cys Phe Asn GlyGly Thr Cys Val Asp Gly Val Ser 930 935 940 Ser Phe Ser Cys Leu Cys ArgPro Gly Tyr Thr Gly Thr His Cys Gln 945 950 955 960 Tyr Glu Ala Asp ProCys Phe Ser Arg Pro Cys Leu His Gly Gly Ile 965 970 975 Cys Asn Pro ThrHis Pro Gly Phe Glu Cys Thr Cys Arg Glu Gly Phe 980 985 990 Thr Gly SerGln Cys Gln Asn Pro Val Asp Trp Cys Ser Gln Ala Pro 995 1000 1005 CysGln Asn Gly Gly Arg Cys Val Gln Thr Gly Ala Tyr Cys Ile Cys 1010 10151020 Pro Pro Gly Trp Ser Gly Arg Leu Cys Asp Ile Gln Ser Leu Pro Cys1025 1030 1035 1040 Thr Glu Ala Ala Ala Gln Met Gly Val Arg Leu Glu GlnLeu Cys Gln 1045 1050 1055 Glu Gly Gly Lys Cys Ile Asp Lys Gly Arg SerHis Tyr Cys Val Cys 1060 1065 1070 Pro Glu Gly Arg Thr Gly Ser His CysGlu His Glu Val Asp Pro Cys 1075 1080 1085 Thr Ala Gln Pro Cys Gln HisGly Gly Thr Cys Arg Gly Tyr Met Gly 1090 1095 1100 Gly Tyr Val Cys GluCys Pro Ala Gly Tyr Ala Gly Asp Ser Cys Glu 1105 1110 1115 1120 Asp AsnIle Asp Glu Cys Ala Ser Gln Pro Cys Gln Asn Gly Gly Ser 1125 1130 1135Cys Ile Asp Leu Val Ala Arg Tyr Leu Cys Ser Cys Pro Pro Gly Thr 11401145 1150 Leu Gly Val Leu Cys Glu Ile Asn Glu Asp Asp Cys Asp Leu GlyPro 1155 1160 1165 Ser Leu Asp Ser Gly Val Gln Cys Leu His Asn Gly ThrCys Val Asp 1170 1175 1180 Leu Val Gly Gly Phe Arg Cys Asn Cys Pro ProGly Tyr Thr Gly Leu 1185 1190 1195 1200 His Cys Glu Ala Asp Ile Asn GluCys Arg Pro Gly Ala Cys His Ala 1205 1210 1215 Ala His Thr Arg Asp CysLeu Gln Asp Pro Gly Gly His Phe Arg Cys 1220 1225 1230 Val Cys His ProGly Phe Thr Gly Pro Arg Cys Gln Ile Ala Leu Ser 1235 1240 1245 Pro CysGlu Ser Gln Pro Cys Gln His Gly Gly Gln Cys Arg His Ser 1250 1255 1260Leu Gly Arg Gly Gly Gly Leu Thr Phe Thr Cys His Cys Val Pro Pro 12651270 1275 1280 Phe Trp Gly Leu Arg Cys Glu Arg Val Ala Arg Ser Cys ArgGlu Leu 1285 1290 1295 Gln Cys Pro Val Gly Ile Pro Cys Gln Gln Thr AlaArg Gly Pro Arg 1300 1305 1310 Cys Ala Cys Pro Pro Gly Leu Ser Gly ProSer Cys Arg Val Ser Arg 1315 1320 1325 Ala Ser Pro Ser Gly Ala Thr AsnAla Ser Cys Ala Ser Ala Pro Cys 1330 1335 1340 Leu His Gly Gly Ser CysLeu Pro Val Gln Ser Val Pro Phe Phe Arg 1345 1350 1355 1360 Cys Val CysAla Pro Gly Trp Gly Gly Pro Arg Cys Glu Thr Pro Ser 1365 1370 1375 AlaAla Pro Glu Val Pro Glu Glu Pro Arg Cys Pro Arg Ala Ala Cys 1380 13851390 Gln Ala Lys Arg Gly Asp Gln Asn Cys Asp Arg Glu Cys Asn Thr Pro1395 1400 1405 Gly Cys Gly Trp Asp Gly Gly Asp Cys Ser Leu Asn Val AspAsp Pro 1410 1415 1420 Trp Arg Gln Cys Glu Ala Leu Gln Cys Trp Arg LeuPhe Asn Asn Ser 1425 1430 1435 1440 Arg Cys Asp Pro Ala Cys Ser Ser ProAla Cys Leu Tyr Asp Asn Phe 1445 1450 1455 Asp Cys Tyr Ser Gly Gly ArgAsp Arg Thr Cys Asn Pro Val Tyr Glu 1460 1465 1470 Lys Tyr Cys Ala AspHis Phe Ala Asp Gly Arg Cys Asp Gln Gly Cys 1475 1480 1485 Asn Thr GluGlu Cys Gly Trp Asp Gly Leu Asp Cys Ala Ser Glu Val 1490 1495 1500 ProAla Leu Leu Ala Arg Gly Val Leu Val Leu Thr Val Leu Leu Pro 1505 15101515 1520 Pro Glu Glu Leu Leu Arg Ser Ser Ala Asp Phe Leu Gln Arg LeuSer 1525 1530 1535 Ala Ile Leu Arg Thr Ser Leu Arg Phe Arg Leu Asp AlaArg Gly Gln 1540 1545 1550 Ala Met Val Phe Pro Tyr His Arg Pro Ser ProGly Ser Glu Ser Arg 1555 1560 1565 Val Arg Arg Glu Leu Gly Pro Glu ValIle Gly Ser Val Val Met Leu 1570 1575 1580 Glu Ile Asp Asn Arg Leu CysLeu Gln Ser Ala Glu Asn Asp His Cys 1585 1590 1595 1600 Phe Pro Asp AlaGln Ser Ala Ala Asp Tyr Leu Gly Ala Leu Ser Ala 1605 1610 1615 Val GluArg Leu Asp Phe Pro Tyr Pro Leu Arg Asp Val Arg Gly Glu 1620 1625 1630Pro Leu Glu Ala Pro Glu Gln Ser Val Pro Leu Leu Pro Leu Leu Val 16351640 1645 Ala Gly Ala Val Phe Leu Leu Ile Ile Phe Ile Leu Gly Val MetVal 1650 1655 1660 Ala Arg Arg Lys Arg Glu His Ser Thr Leu Trp Phe ProGlu Gly Phe 1665 1670 1675 1680 Ala Leu His Lys Asp Ile Ala Ala Gly HisLys Gly Arg Arg Glu Pro 1685 1690 1695 Val Gly Gln Asp Ala Leu Gly MetLys Asn Met Ala Lys Gly Glu Ser 1700 1705 1710 Leu Met Gly Glu Val ValThr Asp Leu Asn Asp Ser Glu Cys Pro Glu 1715 1720 1725 Ala Lys Arg LeuLys Val Glu Glu Pro Gly Met Gly Ala Glu Glu Pro 1730 1735 1740 Glu AspCys Arg Gln Trp Thr Gln His His Leu Val Ala Ala Asp Ile 1745 1750 17551760 Arg Val Ala Pro Ala Thr Ala Leu Thr Pro Pro Gln Gly Asp Ala Asp1765 1770 1775 Ala Asp Gly Val Asp Val Asn Val Arg Gly Pro Asp Gly PheThr Pro 1780 1785 1790 Leu Met Leu Ala Ser Phe Cys Gly Gly Ala Leu GluPro Met Pro Ala 1795 1800 1805 Glu Glu Asp Glu Ala Asp Asp Thr Ser AlaSer Ile Ile Ser Asp Leu 1810 1815 1820 Ile Cys Gln Gly Ala Gln Leu GlyAla Arg Thr Asp Arg Thr Gly Glu 1825 1830 1835 1840 Thr Ala Leu His LeuAla Ala Arg Tyr Ala Arg Ala Asp Ala Ala Lys 1845 1850 1855 Arg Leu LeuAsp Ala Gly Ala Asp Thr Asn Ala Gln Asp His Ser Gly 1860 1865 1870 ArgThr Pro Leu His Thr Ala Val Thr Ala Asp Ala Gln Gly Val Phe 1875 18801885 Gln Ile Leu Ile Arg Asn Arg Ser Thr Asp Leu Asp Ala Arg Met Ala1890 1895 1900 Asp Gly Ser Thr Ala Leu Ile Leu Ala Ala Arg Leu Ala ValGlu Gly 1905 1910 1915 1920 Met Val Glu Glu Leu Ile Ala Ser His Ala AspVal Asn Ala Val Asp 1925 1930 1935 Glu Leu Gly Lys Ser Ala Leu His TrpAla Ala Ala Val Asn Asn Val 1940 1945 1950 Glu Ala Thr Leu Ala Leu LeuLys Asn Gly Ala Asn Lys Asp Met Gln 1955 1960 1965 Asp Ser Lys Glu GluThr Pro Leu Phe Leu Ala Ala Arg Glu Gly Ser 1970 1975 1980 Tyr Glu AlaAla Lys Leu Leu Leu Asp His Leu Ala Asn Arg Glu Ile 1985 1990 1995 2000Thr Asp His Leu Asp Arg Leu Pro Arg Asp Val Ala Gln Glu Arg Leu 20052010 2015 His Gln Asp Ile Val Arg Leu Leu Asp Gln Pro Ser Gly Pro ArgSer 2020 2025 2030 Pro Ser Gly Pro His Gly Leu Gly Pro Leu Leu Cys ProPro Gly Ala 2035 2040 2045 Phe Leu Pro Gly Leu Lys Ala Val Gln Ser GlyThr Lys Lys Ser Arg 2050 2055 2060 Arg Pro Pro Gly Lys Thr Gly Leu GlyPro Gln Gly Thr Arg Gly Arg 2065 2070 2075 2080 Gly Lys Lys Leu Thr LeuAla Cys Pro Gly Pro Leu Ala Asp Ser Ser 2085 2090 2095 Val Thr Leu SerPro Val Asp Ser Leu Asp Ser Pro Arg Pro Phe Ser 2100 2105 2110 Gly ProPro Ala Ser Pro Gly Gly Phe Pro Leu Glu Gly Pro Tyr Ala 2115 2120 2125Thr Thr Ala Thr Ala Val Ser Leu Ala Gln Leu Gly Ala Ser Arg Ala 21302135 2140 Gly Pro Leu Gly Arg Gln Pro Pro Gly Gly Cys Val Leu Ser PheGly 2145 2150 2155 2160 Leu Leu Asn Pro Val Ala Val Pro Leu Asp Trp AlaArg Leu Pro Pro 2165 2170 2175 Pro Ala Pro Pro Gly Pro Ser Phe Leu LeuPro Leu Ala Pro Gly Pro 2180 2185 2190 Gln Leu Leu Asn Pro Gly Ala ProVal Ser Pro Gln Glu Arg Pro Pro 2195 2200 2205 Pro Tyr Leu Ala Ala ProGly His Gly Glu Glu Tyr Pro Ala Ala Gly 2210 2215 2220 Thr Arg Ser SerPro Thr Lys Ala Arg Phe Leu Arg Val Pro Ser Glu 2225 2230 2235 2240 HisPro Tyr Leu Thr Pro Ser Pro Glu Ser Pro Glu His Trp Ala Ser 2245 22502255 Pro Ser Pro Pro Ser Leu Ser Asp Trp Ser Asp Ser Thr Pro Ser Pro2260 2265 2270 Ala Thr Ala Thr Asn Ala Thr Ala Ser Gly Ala Leu Pro AlaGln Pro 2275 2280 2285 His Pro Ile Ser Val Pro Ser Leu Pro Gln Ser GlnThr Gln Leu Gly 2290 2295 2300 Pro Gln Pro Glu Val Thr Pro Lys Arg GlnVal Met Ala 2305 2310 2315 27 2471 PRT Drosophila melanogaster 27 MetPro Ala Leu Arg Pro Ala Ala Leu Arg Ala Leu Leu Trp Leu Trp 1 5 10 15Leu Cys Gly Ala Gly Pro Ala His Ala Leu Gln Cys Arg Gly Gly Gln 20 25 30Glu Pro Cys Val Asn Glu Gly Thr Cys Val Thr Tyr His Asn Gly Thr 35 40 45Gly Tyr Cys Arg Cys Pro Glu Gly Phe Leu Gly Glu Tyr Cys Gln His 50 55 60Arg Asp Pro Cys Glu Lys Asn Arg Cys Gln Asn Gly Gly Thr Cys Val 65 70 7580 Thr Gln Ala Met Leu Gly Lys Ala Thr Cys Arg Cys Ala Pro Gly Phe 85 9095 Thr Gly Glu Asp Cys Gln Tyr Ser Thr Ser His Pro Cys Phe Val Ser 100105 110 Arg Pro Cys Gln Asn Gly Gly Thr Cys His Met Leu Ser Trp Asp Thr115 120 125 Tyr Glu Cys Thr Cys Gln Val Gly Phe Thr Gly Lys Gln Cys GlnTrp 130 135 140 Thr Asp Val Cys Leu Ser His Pro Cys Glu Asn Gly Ser ThrCys Ser 145 150 155 160 Ser Val Ala Asn Gln Phe Ser Cys Arg Cys Pro AlaGly Ile Thr Gly 165 170 175 Gln Lys Cys Asp Ala Asp Ile Asn Glu Cys AspIle Pro Gly Arg Cys 180 185 190 Gln His Gly Gly Thr Cys Leu Asn Leu ProGly Ser Tyr Arg Cys Gln 195 200 205 Cys Pro Gln Arg Phe Thr Gly Gln HisCys Asp Ser Pro Tyr Val Pro 210 215 220 Cys Ala Pro Ser Pro Cys Val AsnGly Gly Thr Cys Arg Gln Thr Gly 225 230 235 240 Asp Phe Thr Ser Glu CysHis Cys Leu Pro Gly Phe Glu Gly Ser Asn 245 250 255 Cys Glu Arg Asn IleAsp Asp Cys Pro Asn His Lys Cys Gln Asn Gly 260 265 270 Gly Val Cys ValAsp Gly Val Asn Thr Tyr Asn Cys Arg Cys Pro Pro 275 280 285 Gln Trp ThrGly Gln Phe Cys Thr Glu Asp Val Asp Glu Cys Leu Leu 290 295 300 Gln ProAsn Ala Cys Gln Asn Gly Gly Thr Cys Thr Asn Arg Asn Gly 305 310 315 320Gly Tyr Gly Cys Val Cys Val Asn Gly Trp Ser Gly Asp Asp Cys Ser 325 330335 Glu Asn Ile Asp Asp Cys Ala Phe Ala Ser Cys Thr Pro Gly Ser Thr 340345 350 Cys Ile Asp Arg Val Ala Ser Phe Ser Cys Leu Cys Pro Glu Gly Lys355 360 365 Ala Gly Leu Leu Cys His Leu Asp Asp Ala Cys Ile Ser Asn ProCys 370 375 380 His Lys Gly Ala Leu Cys Asp Thr Asn Pro Leu Asn Gly GlnTyr Ile 385 390 395 400 Cys Thr Cys Pro Gln Ala Tyr Lys Gly Ala Asp CysThr Glu Asp Val 405 410 415 Asp Glu Cys Ala Met Ala Asn Ser Asn Pro CysGlu His Ala Gly Lys 420 425 430 Cys Val Asn Thr Asp Gly Ala Phe His CysGlu Cys Leu Lys Gly Tyr 435 440 445 Ala Gly Pro Arg Cys Glu Met Asp IleAsn Glu Cys His Ser Asp Pro 450 455 460 Cys Gln Asn Asp Ala Thr Cys LeuAsp Lys Ile Gly Gly Phe Thr Cys 465 470 475 480 Leu Cys Met Pro Gly PheLys Gly Val His Cys Glu Leu Glu Val Asn 485 490 495 Glu Cys Gln Ser AsnPro Cys Val Asn Asn Gly Gln Cys Val Asp Lys 500 505 510 Val Asn Arg PheGln Cys Leu Cys Pro Pro Gly Phe Thr Gly Pro Val 515 520 525 Cys Gln IleAsp Ile Asp Asp Cys Ser Ser Thr Pro Cys Leu Asn Gly 530 535 540 Ala LysCys Ile Asp His Pro Asn Gly Tyr Glu Cys Gln Cys Ala Thr 545 550 555 560Gly Phe Thr Gly Thr Leu Cys Asp Glu Asn Ile Asp Asn Cys Asp Pro 565 570575 Asp Pro Cys His His Gly Gln Cys Gln Asp Gly Ile Asp Ser Tyr Thr 580585 590 Cys Ile Cys Asn Pro Gly Tyr Met Gly Ala Ile Cys Ser Asp Gln Ile595 600 605 Asp Glu Cys Tyr Ser Ser Pro Cys Leu Asn Asp Gly Arg Cys IleAsp 610 615 620 Leu Val Asn Gly Tyr Gln Cys Asn Cys Gln Pro Gly Thr SerGly Leu 625 630 635 640 Asn Cys Glu Ile Asn Phe Asp Asp Cys Ala Ser AsnPro Cys Leu His 645 650 655 Gly Ala Cys Val Asp Gly Ile Asn Arg Tyr SerCys Val Cys Ser Pro 660 665 670 Gly Phe Thr Gly Gln Arg Cys Asn Ile AspIle Asp Glu Cys Ala Ser 675 680 685 Asn Pro Cys Arg Lys Asp Ala Thr CysIle Asn Asp Val Asn Gly Phe 690 695 700 Arg Cys Met Cys Pro Glu Gly ProHis His Pro Ser Cys Tyr Ser Gln 705 710 715 720 Val Asn Glu Cys Leu SerSer Pro Cys Ile His Gly Asn Cys Thr Gly 725 730 735 Gly Leu Ser Gly TyrLys Cys Leu Cys Asp Ala Gly Trp Val Gly Ile 740 745 750 Asn Cys Glu ValAsp Lys Asn Glu Cys Leu Ser Asn Pro Cys Gln Asn 755 760 765 Gly Gly ThrCys Asn Asn Leu Val Asn Gly Tyr Arg Cys Thr Cys Lys 770 775 780 Lys GlyPhe Lys Gly Tyr Asn Cys Gln Val Asn Ile Asp Glu Cys Ala 785 790 795 800Ser Asn Pro Cys Leu Asn Gln Gly Thr Cys Leu Asp Asp Val Ser Gly 805 810815 Tyr Thr Cys His Cys Met Leu Pro Tyr Thr Gly Lys Asn Cys Gln Thr 820825 830 Val Leu Ala Pro Cys Ser Pro Asn Pro Cys Glu Asn Ala Ala Val Cys835 840 845 Lys Glu Ala Pro Asn Phe Glu Ser Phe Thr Cys Leu Cys Ala ProGly 850 855 860 Trp Gln Gly Gln Arg Cys Thr Val Asp Val Asp Glu Cys ValSer Lys 865 870 875 880 Pro Cys Met Asn Asn Gly Ile Cys His Asn Thr GlnGly Ser Tyr Met 885 890 895 Cys Glu Cys Pro Pro Gly Phe Ser Gly Met AspCys Glu Glu Asp Ile 900 905 910 Asn Asp Cys Leu Ala Asn Pro Cys Gln AsnGly Gly Ser Cys Val Asp 915 920 925 Lys Val Asn Thr Phe Ser Cys Leu CysLeu Pro Gly Phe Val Gly Asp 930 935 940 Lys Cys Gln Thr Asp Met Asn GluCys Leu Ser Glu Pro Cys Lys Asn 945 950 955 960 Gly Gly Thr Cys Ser AspTyr Val Asn Ser Tyr Thr Cys Thr Cys Pro 965 970 975 Ala Gly Phe His GlyVal His Cys Glu Asn Asn Ile Asp Glu Cys Thr 980 985 990 Glu Ser Ser CysPhe Asn Gly Gly Thr Cys Val Asp Gly Ile Asn Ser 995 1000 1005 Phe SerCys Leu Cys Pro Val Gly Phe Thr Gly Pro Phe Cys Leu His 1010 1015 1020Asp Ile Asn Glu Cys Ser Ser Asn Pro Cys Leu Asn Ser Gly Thr Cys 10251030 1035 1040 Val Asp Gly Leu Gly Thr Tyr Arg Cys Thr Cys Pro Leu GlyTyr Thr 1045 1050 1055 Gly Lys Asn Cys Gln Thr Leu Val Asn Leu Cys SerPro Ser Pro Cys 1060 1065 1070 Lys Asn Lys Gly Thr Cys Ala Gln Glu LysAla Arg Pro Arg Cys Leu 1075 1080 1085 Cys Pro Pro Gly Trp Asp Gly AlaTyr Cys Asp Val Leu Asn Val Ser 1090 1095 1100 Cys Lys Ala Ala Ala LeuGln Lys Gly Val Pro Val Glu His Leu Cys 1105 1110 1115 1120 Gln His SerGly Ile Cys Ile Asn Ala Gly Asn Thr His His Cys Gln 1125 1130 1135 CysPro Leu Gly Tyr Thr Gly Ser Tyr Cys Glu Glu Gln Leu Asp Glu 1140 11451150 Cys Ala Ser Asn Pro Cys Gln His Gly Ala Thr Cys Ser Asp Phe Ile1155 1160 1165 Gly Gly Tyr Arg Cys Glu Cys Val Pro Gly Tyr Gln Gly ValAsn Cys 1170 1175 1180 Glu Tyr Glu Val Asp Glu Cys Gln Asn Gln Pro CysGln Asn Gly Gly 1185 1190 1195 1200 Thr Cys Ile Asp Leu Val Asn His PheLys Cys Ser Cys Pro Pro Gly 1205 1210 1215 Thr Arg Gly Leu Leu Cys GluGlu Asn Ile Asp Asp Cys Ala Gly Ala 1220 1225 1230 Pro His Cys Leu AsnGly Gly Gln Cys Val Asp Arg Ile Gly Gly Tyr 1235 1240 1245 Ser Cys ArgCys Leu Pro Gly Phe Ala Gly Glu Arg Cys Glu Gly Asp 1250 1255 1260 IleAsn Glu Cys Leu Ser Asn Pro Cys Ser Ser Glu Gly Ser Leu Asp 1265 12701275 1280 Cys Ile Gln Leu Lys Asn Asn Tyr Gln Cys Val Cys Arg Ser AlaPhe 1285 1290 1295 Thr Gly Arg His Cys Glu Thr Phe Leu Asp Val Cys ProGln Lys Pro 1300 1305 1310 Cys Leu Asn Gly Gly Thr Cys Ala Val Ala SerAsn Val Pro Asp Gly 1315 1320 1325 Phe Ile Cys Arg Cys Pro Pro Gly PheSer Gly Ala Arg Cys Gln Ser 1330 1335 1340 Ser Cys Gly Gln Val Lys CysArg Arg Gly Glu Gln Cys Val His Thr 1345 1350 1355 1360 Ala Ser Gly ProHis Cys Phe Cys Pro Asn His Lys Asp Cys Glu Ser 1365 1370 1375 Gly CysAla Ser Asn Pro Cys Gln His Gly Gly Thr Cys Tyr Pro Gln 1380 1385 1390Arg Gln Pro Pro Tyr Tyr Ser Cys Arg Cys Ser Pro Pro Phe Trp Gly 13951400 1405 Ser His Cys Glu Ser Tyr Thr Ala Pro Thr Ser Thr Pro Pro AlaThr 1410 1415 1420 Cys Leu Ser Gln Tyr Cys Ala Asp Lys Ala Arg Asp GlyIle Cys Asp 1425 1430 1435 1440 Glu Ala Cys Asn Ser His Ala Cys Gln TrpAsp Gly Gly Asp Cys Ser 1445 1450 1455 Leu Thr Met Glu Asp Pro Trp AlaAsn Cys Thr Ser Ser Leu Arg Cys 1460 1465 1470 Trp Glu Tyr Ile Asn AsnGln Cys Asp Glu Leu Cys Asn Thr Ala Glu 1475 1480 1485 Cys Leu Phe AspAsn Phe Glu Cys Gln Arg Asn Ser Lys Thr Cys Lys 1490 1495 1500 Tyr AspLys Tyr Cys Ala Asp His Phe Lys Asp Asn His Cys Asp Lys 1505 1510 15151520 Gly Cys Asn Asn Glu Glu Cys Gly Trp Asp Gly Leu Asp Cys Ala Ala1525 1530 1535 Asp Gln Pro Glu Asn Leu Ala Glu Gly Ile Leu Val Ile ValVal Leu 1540 1545 1550 Leu Pro Pro Glu Gln Leu Leu Gln Asp Ser Arg SerPhe Leu Arg Ala 1555 1560 1565 Leu Gly Thr Leu Leu His Thr Asn Leu ArgIle Lys Gln Asp Ser Gln 1570 1575 1580 Gly Ala Leu Met Val Tyr Pro TyrTyr Gly Glu Lys Ser Ala Ala Met 1585 1590 1595 1600 Lys Lys Gln Lys ValAla Arg Arg Ser Leu Pro Asp Glu Gln Glu Gln 1605 1610 1615 Glu Ile IleGly Ser Lys Val Phe Leu Glu Ile Asp Asn Arg Gln Cys 1620 1625 1630 ValGln Asp Ser Asp Gln Cys Phe Lys Asn Thr Asp Ala Ala Ala Ala 1635 16401645 Leu Leu Ala Ser His Ala Ile Gln Gly Thr Leu Ser Tyr Pro Leu Val1650 1655 1660 Ser Val Val Ser Glu Ser Glu Asp Pro Arg Asn Thr Pro LeuLeu Tyr 1665 1670 1675 1680 Leu Leu Ala Val Ala Val Val Ile Ile Leu PheLeu Ile Leu Leu Gly 1685 1690 1695 Val Ile Met Ala Lys Arg Lys Arg LysHis Gly Phe Leu Trp Leu Pro 1700 1705 1710 Glu Gly Phe Thr Leu Arg ArgAsp Ser Ser Asn His Lys Arg Arg Glu 1715 1720 1725 Pro Val Gly Gln AspAla Val Gly Leu Lys Asn Leu Ser Val Gln Val 1730 1735 1740 Ser Glu AlaAsn Leu Ile Gly Ser Thr Thr Ser Glu His Trp Gly Asp 1745 1750 1755 1760Asp Glu Gly Pro Gln Pro Lys Lys Ala Lys Ala Glu Asp Asp Glu Ala 17651770 1775 Leu Leu Ser Glu Asp Asp Pro Val Asp Arg Arg Pro Trp Thr GlnGln 1780 1785 1790 His Leu Glu Ala Ala Asp Ile Arg Arg Thr Pro Ser LeuAla Leu Thr 1795 1800 1805 Pro Pro Gln Ala Glu Gln Glu Val Asp Val LeuAsp Val Asn Val Arg 1810 1815 1820 Gly Pro Asp Gly Cys Thr Pro Leu MetLeu Ala Ser Leu Arg Gly Gly 1825 1830 1835 1840 Ser Ser Asp Leu Ser AspGlu Asp Glu Asp Ala Glu Asp Ser Ser Ala 1845 1850 1855 Asn Ile Ile ThrAsp Leu Val Tyr Gln Gly Ala Ser Leu Gln Ala Gln 1860 1865 1870 Thr AspArg Thr Gly Glu Met Ala Leu His Leu Ala Ala Arg Tyr Ser 1875 1880 1885Arg Ala Asp Ala Ala Lys Arg Leu Leu Asp Ala Gly Ala Asp Ala Asn 18901895 1900 Ala Gln Asp Asn Met Gly Arg Cys Pro Leu His Ala Ala Val AlaAla 1905 1910 1915 1920 Asp Ala Gln Gly Val Phe Gln Ile Leu Ile Arg AsnArg Val Thr Asp 1925 1930 1935 Leu Asp Ala Arg Met Asn Asp Gly Thr ThrPro Leu Ile Leu Ala Ala 1940 1945 1950 Arg Leu Ala Val Glu Gly Met ValAla Glu Leu Ile Asn Cys Gln Ala 1955 1960 1965 Asp Val Asn Ala Val AspAsp His Gly Lys Ser Ala Leu His Trp Ala 1970 1975 1980 Ala Ala Val AsnAsn Val Glu Ala Thr Leu Leu Leu Leu Lys Asn Gly 1985 1990 1995 2000 AlaAsn Arg Asp Met Gln Asp Asn Lys Glu Glu Thr Pro Leu Phe Leu 2005 20102015 Ala Ala Arg Glu Gly Ser Tyr Glu Ala Ala Lys Ile Leu Leu Asp His2020 2025 2030 Phe Ala Asn Arg Asp Ile Thr Asp His Met Asp Arg Leu ProArg Asp 2035 2040 2045 Val Ala Arg Asp Arg Met His His Asp Ile Val ArgLeu Leu Asp Glu 2050 2055 2060 Tyr Asn Val Thr Pro Ser Pro Pro Gly ThrVal Leu Thr Ser Ala Leu 2065 2070 2075 2080 Ser Pro Val Leu Cys Gly ProAsn Arg Ser Phe Leu Ser Leu Lys His 2085 2090 2095 Thr Pro Met Gly LysLys Ala Arg Arg Pro Asn Thr Lys Ser Thr Met 2100 2105 2110 Pro Thr SerLeu Pro Asn Leu Ala Lys Glu Ala Lys Asp Val Lys Gly 2115 2120 2125 SerArg Arg Lys Lys Cys Leu Asn Glu Lys Val Gln Leu Ser Glu Ser 2130 21352140 Ser Val Thr Leu Ser Pro Val Asp Ser Leu Glu Ser Pro His Thr Tyr2145 2150 2155 2160 Val Ser Asp Ala Thr Ser Ser Pro Met Ile Thr Ser ProGly Ile Leu 2165 2170 2175 Gln Ala Ser Pro Thr Pro Leu Leu Ala Ala AlaPro Ala Ala Pro Val 2180 2185 2190 His Ala Gln His Ala Leu Ser Phe SerAsn Leu His Glu Met Gln Pro 2195 2200 2205 Leu Arg Pro Gly Ala Ser ThrVal Leu Pro Ser Val Ser Gln Leu Leu 2210 2215 2220 Ser His His His IleVal Pro Pro Gly Ser Gly Ser Ala Gly Ser Leu 2225 2230 2235 2240 Gly ArgLeu His Ser Val Pro Val Pro Ser Asp Trp Met Asn Arg Val 2245 2250 2255Glu Met Ser Glu Thr Gln Tyr Ser Glu Met Phe Gly Met Val Leu Ala 22602265 2270 Pro Ala Glu Gly Thr His Pro Gly Met Ala Ala Pro Gln Ser ArgAla 2275 2280 2285 Pro Glu Gly Lys Pro Ile Pro Thr Gln Arg Glu Pro LeuPro Pro Ile 2290 2295 2300 Val Thr Phe Gln Leu Ile Pro Lys Gly Ser LeuAla Gln Ala Ala Gly 2305 2310 2315 2320 Ala Pro Gln Thr Gln Ser Gly CysPro Pro Ala Val Ala Gly Pro Leu 2325 2330 2335 Pro Ser Met Tyr Gln IlePro Glu Met Ala Arg Leu Pro Ser Val Ala 2340 2345 2350 Phe Pro Pro ThrMet Met Pro Gln Gln Glu Gly Gln Val Ala Gln Thr 2355 2360 2365 Ile ValPro Thr Tyr His Pro Phe Pro Ala Ser Val Gly Lys Tyr Pro 2370 2375 2380Thr Pro Pro Ser Gln His Ser Tyr Ala Ser Ser Asn Ala Ala Glu Arg 23852390 2395 2400 Thr Pro Asn His Gly Gly His Leu Gln Gly Glu His Pro TyrLeu Thr 2405 2410 2415 Pro Ser Pro Glu Ser Pro Asp Gln Trp Ser Ser SerSer Pro His Ser 2420 2425 2430 Ala Ser Asp Trp Ser Asp Val Thr Thr SerPro Thr Pro Gly Gly Gly 2435 2440 2445 Gly Gly Gly Gln Arg Gly Pro GlyThr His Met Ser Glu Pro Pro His 2450 2455 2460 Ser Asn Met Gln Val TyrAla 2465 2470 28 2447 PRT Takifugu rubripes 28 Cys Ala Pro Gly Phe LeuGly Glu Tyr Cys Gln His Lys Asp Pro Cys 1 5 10 15 Gln Pro Gly Tyr CysLeu Asn Gly Gly Asn Cys Ser Val Ser Met Ser 20 25 30 Ala Gly Val Pro ValPro Gly Ser Ala Thr Cys Ser Cys Pro Leu Gly 35 40 45 Tyr Ala Gly Gln HisCys Gln Ile Pro Gln Asn Ser Thr Cys Tyr Pro 50 55 60 Asn Asn Pro Cys AlaAsn Arg Gly Ile Cys Thr Leu Leu Pro Phe Asp 65 70 75 80 Lys Tyr Lys CysGlu Cys Ala Arg Gly Trp Thr Gly Pro Gly Cys Glu 85 90 95 Tyr Glu Asp SerCys Leu Ser Ser Pro Cys Ala Asn Gly Gly Thr Cys 100 105 110 Ser Thr LeuSer Gly Gly Ser Tyr Thr Cys Ser Cys Leu Pro Gly Tyr 115 120 125 Thr GlyArg His Cys Leu Asn Asp Thr Asp Glu Cys Ala Ala Thr Pro 130 135 140 SerIle Cys Gln Asn Glu Gly Thr Cys Ile Asn Thr Arg Gly Ser Tyr 145 150 155160 Lys Cys Met Cys Ala Leu Gly Phe Thr Gly Lys His Cys Glu Ser Ser 165170 175 Tyr Ile Pro Cys Ser Pro Ser Pro Cys Leu Asn Gly Gly Thr Cys Asn180 185 190 Gln Asn Ser Glu Thr Ser Tyr Ser Cys His Cys Leu Pro Gly PheAsn 195 200 205 Gly Thr Asn Cys Glu Asn Asn Ile Asp Asp Cys Pro Gly HisGln Cys 210 215 220 Ala Asn Arg Gly Thr Cys Ile Asp Gly Val Asn Thr TyrAsn Cys Gln 225 230 235 240 Cys Pro Pro Glu Trp Thr Gly Gln His Cys ThrGlu Asp Val Asn Glu 245 250 255 Cys His Leu Gln Pro Asn Thr Cys Gln AsnGly Gly Thr Cys Ser Asn 260 265 270 Leu Phe Gly Ser Tyr Val Cys Val CysVal Asn Gly Trp Ser Gly Leu 275 280 285 Asp Cys Ser Glu Asn Ile Asp AspCys Asp Thr Ala Ala Cys Ser Pro 290 295 300 Gly Ser Thr Cys Val Asp ArgVal Ala Ser Phe Val Cys Leu Cys Pro 305 310 315 320 Tyr Gly Lys Thr GlyLeu Leu Cys His Leu Asp Asp Ala Cys Ile Ser 325 330 335 Lys Pro Cys LysGly Gly Ser Lys Cys Asp Thr Asn Pro Ile Ser Gly 340 345 350 Met Phe AsnCys Asn Cys Pro Ser Gly Tyr Thr Gly Ser Thr Cys Ser 355 360 365 Ile AspArg Asp Glu Cys Ser Ile Gly Thr Asn Pro Cys Glu His Gly 370 375 380 GlyGln Cys Val Asn Thr Glu Gly Ser Phe Thr Cys Asn Cys Ala Lys 385 390 395400 Gly Tyr Ala Gly Pro Arg Cys Glu Gln Asp Val Asn Glu Cys Ala Ser 405410 415 Asn Pro Cys Gln Asn Asp Gly Thr Cys Leu Asp Arg Ile Gly Asp Tyr420 425 430 Ser Cys Ile Cys Met Pro Gly Phe Gly Gly Thr His Cys Glu AsnGlu 435 440 445 Leu Asn Glu Cys Leu Ser Ser Pro Cys Leu Asn Arg Gly LysCys Leu 450 455 460 Asp Gln Val Ser Arg Phe Val Cys Glu Cys Pro Ala GlyPhe Ser Gly 465 470 475 480 Glu Met Cys Gln Ile Asp Ile Asp Glu Cys SerSer Thr Pro Cys Leu 485 490 495 Asn Gly Ala Lys Cys Ile Asp Leu Pro AsnGly Tyr Asp Cys Glu Cys 500 505 510 Ala Glu Gly Phe Lys Gly Leu Leu CysGlu Glu Asn Ile Asn Asp Cys 515 520 525 Val Pro Glu Pro Cys His His GlyGln Cys Lys Asp Gly Ile Ala Thr 530 535 540 Phe Ser Cys Glu Cys Tyr AlaGly Tyr Thr Gly Ala Ile Cys Asn Ile 545 550 555 560 Gln Val Gln Glu CysHis Ser Asn Pro Cys Gln Asn Arg Gly Arg Cys 565 570 575 Ile Asp Leu ValAsn Ala Tyr Gln Cys Asn Cys Pro Pro Gly Ile Ser 580 585 590 Gly Val AsnCys Glu Ile Asn Glu Asp Asp Cys Ala Ser Asn Leu Cys 595 600 605 Val TyrGly Glu Cys Gln Asp Gly Ile Asn Glu Tyr Lys Cys Val Cys 610 615 620 SerPro Gly Tyr Thr Gly Asp Lys Cys Asp Val Asp Ile Asn Glu Cys 625 630 635640 Ser Ser Asn Pro Cys Met Ser Gly Gly Thr Cys Val Asp Asn Val Asn 645650 655 Gly Phe His Cys Leu Cys Pro Pro Ser Thr Tyr Gly Leu Leu Cys Leu660 665 670 Ser Gly Thr Asp His Cys Val Ala Gln Pro Cys Val His Gly LysCys 675 680 685 Ile Glu Gln Gln Asn Gly Tyr Phe Cys Gln Cys Glu Ala GlyTrp Val 690 695 700 Gly Gln His Cys Glu Gln Glu Lys Asp Glu Cys Leu ProAsn Pro Cys 705 710 715 720 Gln Asn Gly Gly Ser Cys Leu Asp Arg His AsnGly Phe Thr Cys Val 725 730 735 Cys Gln Ala Gly Tyr Arg Gly Val Asn CysGlu Lys Asn Ile Asp Glu 740 745 750 Cys Thr Ser Gly Pro Cys Leu Asn GlnGly Ile Cys Ile Asp Gly Leu 755 760 765 Asn Ser Tyr Thr Cys Gln Cys ValPro Pro Phe Ala Gly Glu His Cys 770 775 780 Glu Val Glu Leu Asp Pro CysSer Ser Arg Pro Cys Gln Arg Gly Gly 785 790 795 800 Val Cys Leu Pro SerAla Asp Tyr Thr Tyr Phe Thr Cys Arg Cys Pro 805 810 815 Ala Gly Trp GlnGly Leu His Cys Ser Glu Asp Val Asn Glu Cys Lys 820 825 830 Lys Asn ProCys Arg Asn Gly Gly His Cys Ile Asn Ser Pro Gly Ser 835 840 845 Tyr IleCys Lys Cys Pro Ser Gly Tyr Ser Gly His Asn Cys Gln Thr 850 855 860 AspIle Asp Asp Cys Ser Pro Asn Pro Cys Leu Asn Gly Gly Ser Cys 865 870 875880 Val Asp Asp Val Gly Ser Phe Ser Cys Glu Cys Arg Pro Gly Phe Glu 885890 895 Gly Glu His Cys Glu Ile Glu Ala Asp Glu Cys Ala Ser Gln Pro Cys900 905 910 Arg Asn Gly Ala Ile Cys Arg Asp Tyr Val Asn Ser Phe Val CysGlu 915 920 925 Cys Arg Leu Gly Phe Asp Gly Ile Leu Cys Asp His Asn IleLeu Glu 930 935 940 Cys Thr Glu Ser Ser Cys Leu Asn Asn Gly Thr Cys IleAsp Asp Ile 945 950 955 960 Asn Thr Phe Ser Cys Arg Cys Leu Pro Gly PhePhe Gly Thr Phe Cys 965 970 975 Glu Tyr Glu Gln Asn Glu Cys Asp Ser GlnPro Cys Lys Asn Gly Gly 980 985 990 Thr Cys Thr Asp Gly Leu Gly Thr TyrArg Cys Thr Cys Pro Ala Gly 995 1000 1005 Tyr Asn Gly Gln Asn Cys GlnAsn Tyr Val Asn Leu Cys Arg Gln Val 1010 1015 1020 Arg Cys His Asn GlyGly Ser Cys Ser His Thr Gly Ala Thr Ser Trp 1025 1030 1035 1040 Thr CysHis Cys Thr Met Gly Trp Thr Gly Pro Tyr Cys Asp Val Pro 1045 1050 1055Asp Met Ser Cys Arg Asp Phe Ala Ala Arg Lys Gly Leu Glu Glu Glu 10601065 1070 Asn Val Cys Lys Asn Ala Gly Arg Cys Val Asn Val Gly Asn SerHis 1075 1080 1085 Lys Cys Glu Cys Gln Pro Gly Tyr Thr Gly Ser Tyr CysGlu Glu Met 1090 1095 1100 Val Asp Glu Cys Lys Ser Asn Pro Cys Arg AsnGly Ala Thr Cys Lys 1105 1110 1115 1120 Asp Tyr Gln Gly Thr Tyr Glu CysIle Cys Lys Pro Gly Tyr Gln Gly 1125 1130 1135 Val Asn Cys Glu Tyr GluVal Asp Glu Cys His Ser Lys Pro Cys Leu 1140 1145 1150 His Gly Gly ThrCys Ile Asn Leu Ile Asn Arg Phe Thr Cys Val Cys 1155 1160 1165 Pro SerGly Thr His Gly Val Gln Cys Glu Val Asn Val Asp Asp Cys 1170 1175 1180Ala Pro Lys Pro Gly Ser Trp Glu Pro Arg Cys Leu Asn Gly Gly Gln 11851190 1195 1200 Cys Leu Asp Gly Ile Gly Arg Tyr Thr Cys Ser Cys Pro ProGly Phe 1205 1210 1215 Val Gly Glu His Cys Glu Gly Asp Leu Asn Glu CysLeu Ser Gly Pro 1220 1225 1230 Cys His Ala Thr Gly Ser Leu Asp Cys ValGln Leu Val Asn Asp Tyr 1235 1240 1245 Gln Cys Arg Cys Arg Leu Gly TyrThr Gly Arg His Cys Asp Ser Met 1250 1255 1260 Val Asp Leu Cys Leu SerLys Pro Cys Arg Asn Gly Gly Val Cys Ser 1265 1270 1275 1280 Met Asn MetThr Ser Val His Gly Tyr Met Cys Ser Cys Pro Pro Gly 1285 1290 1295 PheIle Gly Phe Asn Cys Gly Glu Ile Glu Gly Tyr Thr Cys Ala Lys 1300 13051310 Leu His Cys Gln Asn Gly Gly Arg Cys Val Glu Ser Ala Gly Gly His1315 1320 1325 Leu Tyr Cys Gln Cys Gln Gln Gly Phe Ser Gly Ala His CysGlu Asn 1330 1335 1340 Ser Gln Trp Cys Pro Trp Pro Cys Gln Asn Gly GlyThr Cys Met Lys 1345 1350 1355 1360 Asp Ser Ala Asn Pro Val Gln Tyr SerCys His Cys Pro Asn Asn Phe 1365 1370 1375 Ser Gly Arg Tyr Cys Glu AsnAsn Val Val Gly Ser Gly Pro Ser Thr 1380 1385 1390 Cys Pro Tyr Leu GlnCys Lys His His Ser Ala Asp Lys Val Cys Asp 1395 1400 1405 Ala Gln CysAsn Asn His Glu Cys Asp Trp Asp Gly Gly Asp Cys Ser 1410 1415 1420 LeuAsn Trp Lys Gln Pro Trp Ser Asn Cys Thr Ala Ser Val Ser Cys 1425 14301435 1440 Trp Asp Leu Phe Lys Asn Gly Arg Cys Asp Lys Glu Cys Asp AsnPro 1445 1450 1455 Gly Cys Leu Phe Asp Gly Phe Glu Cys Gln Lys His LysThr Cys Lys 1460 1465 1470 Tyr Val Tyr Glu Lys Tyr Cys Ala Asp His PheGly Asn Lys Ile Cys 1475 1480 1485 Asp Pro Ser Cys Tyr Thr Lys Ala CysGly Trp Asp Gly Leu Asp Cys 1490 1495 1500 Ala Gly Asp Thr Pro Ala LysIle Val Pro Gly Thr Leu Val Ile Val 1505 1510 1515 1520 Val Leu Leu GlnPro Lys Glu Leu Leu Gly Asp Leu Arg Gly Phe Leu 1525 1530 1535 Arg SerLeu Gly Ala Leu Leu Tyr Thr Asn Leu Gln Val Lys Leu Asp 1540 1545 1550Glu Asn Asn Lys Pro Met Val Tyr Pro Tyr Phe Gly Val Glu Asn His 15551560 1565 Gly Gln Gln Leu Lys Gly Ser Arg Ser Lys Arg Glu Leu Glu LysGlu 1570 1575 1580 Val Ile Gly Ser Val Val His Leu Glu Ile Asp Asn ArgLys Cys Ser 1585 1590 1595 1600 Glu Ser Ser Gly Glu Cys Phe Ser Lys ThrGlu Glu Val Ala Ser Phe 1605 1610 1615 Leu Ala Ala Ala His Ile Lys AlaAsp Leu Pro Tyr Pro Leu Val Ser 1620 1625 1630 Val Asn Ser Ser Pro AlaVal Pro Ile Arg Glu Thr His Ile Leu Pro 1635 1640 1645 Tyr Leu Val GlyVal Ser Val Val Ile Leu Leu Leu Ile Val Val Leu 1650 1655 1660 Gly MetLeu Ala Ala Lys Arg Lys His Lys His Gly Leu Leu Trp Leu 1665 1670 16751680 Pro Asp Gly Phe Met Ala Asn Lys Asn Asp Lys Arg Arg Glu Pro Val1685 1690 1695 Gly Gln Asp Asp Phe Asp Leu Lys Asn Phe Lys Thr Gln AspGly Ala 1700 1705 1710 Val Leu Asp Gly Gly Gln Ser Gln Arg Trp Leu GluAsp Glu Val Pro 1715 1720 1725 Pro Arg Lys Pro Arg Leu Glu Gly Lys ProLeu Leu Pro Met Ala Met 1730 1735 1740 Asp Gly Gly Val Asp Arg Arg GluTrp Thr Arg Gln His Arg Lys Ala 1745 1750 1755 1760 Ala Asp Ile Ser LeuThr Pro Pro Gln Ala Glu Leu Asp Ser Asp Gly 1765 1770 1775 Val Asp ValAsn Val Lys Gly Pro Asp Gly Phe Thr Pro Leu Met Leu 1780 1785 1790 AlaSer Leu Arg Asn Gly Gly Val Leu Asp Cys Asn Leu His Gly Asp 1795 18001805 Glu Glu Glu Glu Ser Gly Gly Asp Glu Pro Gly Ser Ser Val Ile Ser1810 1815 1820 Asp Leu Ile Ser Gln Gly Ala Ser Leu Ile Ala Gln Thr AspArg Thr 1825 1830 1835 1840 Gly Glu Thr Ala Leu His Leu Ala Ala Arg TyrAla Arg Ala Asp Ala 1845 1850 1855 Ala Lys Arg Leu Leu Asp Ala Gly AlaAsp Pro Asn Ala His Asp Asn 1860 1865 1870 Met Gly Arg Thr Pro Leu HisAla Ala Val Ala Ala Asp Ala Gln Gly 1875 1880 1885 Val Phe Gln Ile LeuIle Arg Asn Arg Ala Thr Glu Leu Asp Ser Arg 1890 1895 1900 Met Asn AspGly Thr Thr Pro Leu Ile Leu Ala Ala Arg Leu Ala Val 1905 1910 1915 1920Glu Gly Met Val Glu Glu Leu Ile His Cys His Ala Asp Ile Asn Ala 19251930 1935 Val Asp Asp His Gly Lys Ser Ala Leu His Trp Ala Ala Ala ValAsn 1940 1945 1950 Asn Val Glu Ala Thr Leu Val Leu Leu Lys Asn Gly AlaAsn Arg Asp 1955 1960 1965 Met Gln Asp Asn Lys Glu Glu Thr Pro Leu PheLeu Ala Ala Arg Glu 1970 1975 1980 Gly Ser Phe Glu Ala Ala Gln Val LeuLeu Asp His Tyr Ser Asn Arg 1985 1990 1995 2000 Asp Ile Thr Asp His MetAsp Arg Leu Pro Arg Asp Thr Ala Gln Glu 2005 2010 2015 Arg Met His HisAsp Ile Val Arg Leu Leu Asp Gln Tyr Asn Val Val 2020 2025 2030 His SerPro His Asn Gly Pro Asn Leu Met Gly Gly Ala Gly Asn Pro 2035 2040 2045Ser Met Met Cys Gly Ala Asn Gly Ala Gly Phe Met Asn Val Arg Ser 20502055 2060 Gly Ala Gln Gly Lys Lys Asn Arg Arg Gly Gly Gly Val Thr AsnVal 2065 2070 2075 2080 Gly Gly Val Gly Gly Gly Pro Lys Glu Leu Lys AspMet Lys Ser Lys 2085 2090 2095 Arg Arg Lys Lys Pro Thr Gly Val Glu GlyPro Gly Ala Ser Ala Gly 2100 2105 2110 Ala Gly Gly Ala Ile Gly Gly ThrAla Ala Asn Gly Val Asn Ala Asn 2115 2120 2125 Gly Val Lys Thr Ala GlyAla Leu Pro Glu Ser Ser Val Thr Met Ser 2130 2135 2140 Pro Val Asp SerLeu Glu Ser Pro His Ser Phe Leu Gly Asp Val Ser 2145 2150 2155 2160 GlyThr Val Ser Thr Thr Ala Asn Ser Pro Pro Leu Leu Ser Ser Pro 2165 21702175 Thr Thr Arg Pro Met Leu Pro Pro Val Ser His Met Leu Gly Gln Gln2180 2185 2190 Gln Gly Trp Val Gly Thr Thr Lys His Pro Tyr Ser Asp HisMet Phe 2195 2200 2205 Ser Leu Ile Pro His Gln Ile Gly Gly Ser His ThrGly Met Gly His 2210 2215 2220 Ser Arg Gly Pro Met Phe Thr Pro Met AsnVal Thr Met Ser Arg Glu 2225 2230 2235 2240 Gln Leu Pro Pro Ile Val ThrPhe Gln Met Met Ala Pro Gly Gly Gly 2245 2250 2255 Gln Gly Met Leu LysGln Ser Gln Thr Gly Gln Val Gln Val Thr Gln 2260 2265 2270 Ser Gln AsnGln Ser His Ser Gln Gln Gly Pro Gly His Leu His Cys 2275 2280 2285 AlaGln Ser Met Met Tyr Gln Met Asn Glu Gln Met Gly Ile Gly His 2290 22952300 Gly Leu Pro His Thr Val Gln His Pro His Thr Ile Gly His Gly His2305 2310 2315 2320 Ala Gly Met Glu Gly Gln Ser Arg Gln Leu Pro Ser TyrGln Pro Met 2325 2330 2335 Gln Ser Pro Val Asp Lys Tyr Pro Thr Pro ProSer Gln His Ser Tyr 2340 2345 2350 Thr Thr Thr Gly Ser Glu Gly Thr ThrPro Gly His Ser Ala His Pro 2355 2360 2365 Pro Ser Glu His Pro Tyr LeuThr Pro Ser Pro Asp Ser Pro Asp Pro 2370 2375 2380 Trp Ser Ser Ser SerPro His Ser Asn Ser Asp Trp Ser Asp Ile Thr 2385 2390 2395 2400 Thr SerPro Thr Pro Leu Gly Asn Leu Thr Thr His Cys Arg Leu His 2405 2410 2415Thr Ala His Thr Phe Gln Ser Arg Cys Ser Cys Ser Pro Ser Pro Asn 24202425 2430 Arg Phe Ser Arg Ala Pro Ser Ser Leu Ser Trp Gly Thr Cys Arg2435 2440 2445 29 2531 PRT Rattus norvegicus 29 Met Pro Arg Leu Leu AlaPro Leu Leu Cys Leu Thr Leu Leu Pro Ala 1 5 10 15 Leu Ala Ala Arg GlyLeu Arg Cys Ser Gln Pro Ser Gly Thr Cys Leu 20 25 30 Asn Gly Gly Arg CysGlu Val Ala Asn Gly Thr Glu Ala Cys Val Cys 35 40 45 Ser Gly Ala Phe ValGly Gln Arg Cys Gln Asp Pro Ser Pro Cys Leu 50 55 60 Ser Thr Pro Cys LysAsn Ala Gly Thr Cys Tyr Val Val Asp His Gly 65 70 75 80 Gly Ile Val AspTyr Ala Cys Ser Cys Pro Leu Gly Phe Ser Gly Pro 85 90 95 Leu Cys Leu ThrPro Leu Ala Asn Ala Cys Leu Ala Asn Pro Cys Arg 100 105 110 Asn Gly GlyThr Cys Asp Leu Leu Thr Leu Thr Glu Tyr Lys Cys Arg 115 120 125 Cys ProPro Gly Trp Ser Gly Lys Ser Cys Gln Gln Ala Asp Pro Cys 130 135 140 AlaSer Asn Pro Cys Ala Asn Gly Gly Gln Cys Leu Pro Phe Glu Ser 145 150 155160 Ser Tyr Ile Cys Gly Cys Pro Pro Gly Phe His Gly Pro Thr Cys Arg 165170 175 Gln Asp Val Asn Glu Cys Ser Gln Asn Pro Gly Leu Cys Arg His Gly180 185 190 Gly Thr Cys His Asn Glu Ile Gly Ser Tyr Arg Cys Ala Cys ArgAla 195 200 205 Thr His Thr Gly Pro His Cys Glu Leu Pro Tyr Val Pro CysSer Pro 210 215 220 Ser Pro Cys Gln Asn Gly Gly Thr Cys Arg Pro Thr GlyAsp Thr Thr 225 230 235 240 His Glu Cys Ala Cys Leu Pro Gly Phe Ala GlyGln Asn Cys Glu Glu 245 250 255 Asn Val Asp Asp Cys Pro Gly Asn Asn CysLys Asn Gly Gly Ala Cys 260 265 270 Val Asp Gly Val Asn Thr Tyr Asn CysArg Cys Pro Pro Glu Trp Thr 275 280 285 Gly Gln Tyr Cys Thr Glu Asp ValAsp Glu Cys Gln Leu Met Pro Asn 290 295 300 Ala Cys Gln Asn Ala Gly ThrCys His Asn Ser His Gly Gly Tyr Asn 305 310 315 320 Cys Val Cys Val AsnGly Trp Thr Gly Glu Asp Cys Ser Asp Asn Ile 325 330 335 Asp Asp Cys AlaSer Ala Ala Cys Phe Gln Gly Ala Thr Cys His Asp 340 345 350 Arg Val AlaSer Phe Tyr Cys Glu Cys Pro His Gly Arg Thr Gly Leu 355 360 365 Leu CysHis Leu Asn Asp Ala Cys Ile Ser Asn Pro Cys Asn Glu Gly 370 375 380 SerAsn Cys Asp Thr Asn Pro Val Asn Gly Lys Ala Ile Cys Thr Cys 385 390 395400 Pro Arg Gly Tyr Thr Gly Pro Ala Cys Ser Gln Asp Val Asp Glu Cys 405410 415 Ala Leu Gly Ala Asn Pro Cys Glu His Ala Gly Lys Cys Leu Asn Thr420 425 430 Leu Gly Ser Phe Glu Cys Gln Cys Leu Gln Gly Tyr Thr Gly ProArg 435 440 445 Cys Glu Ile Asp Val Asn Glu Cys Ile Ser Asn Pro Cys GlnAsn Asp 450 455 460 Ala Thr Cys Leu Asp Gln Ile Gly Glu Phe Gln Cys IleCys Met Pro 465 470 475 480 Gly Tyr Glu Gly Val Tyr Cys Glu Ile Asn ThrAsp Glu Cys Ala Ser 485 490 495 Ser Pro Cys Leu His Asn Gly Arg Cys ValAsp Lys Ile Asn Glu Phe 500 505 510 Leu Cys Gln Cys Pro Lys Gly Phe SerGly His Leu Cys Gln Tyr Asp 515 520 525 Val Asp Glu Cys Ala Ser Thr ProCys Lys Asn Gly Ala Lys Cys Leu 530 535 540 Asp Gly Pro Asn Thr Tyr ThrCys Val Cys Thr Glu Gly Tyr Thr Gly 545 550 555 560 Thr His Cys Glu ValAsp Ile Asp Glu Cys Asp Pro Asp Pro Cys His 565 570 575 Ile Gly Leu CysLys Asp Gly Val Ala Thr Phe Thr Cys Leu Cys Gln 580 585 590 Pro Gly TyrThr Gly His His Cys Glu Thr Asn Ile Asn Glu Cys His 595 600 605 Ser GlnPro Cys Arg His Gly Gly Thr Cys Gln Asp Arg Asp Asn Tyr 610 615 620 TyrLeu Cys Leu Cys Leu Lys Gly Thr Thr Gly Pro Asn Cys Glu Ile 625 630 635640 Asn Leu Asp Asp Cys Ala Ser Asn Pro Cys Asp Ser Gly Thr Cys Leu 645650 655 Asp Lys Ile Asp Gly Tyr Glu Cys Ala Cys Glu Pro Gly Tyr Thr Gly660 665 670 Ser Met Cys Asn Val Asn Ile Asp Glu Cys Ala Gly Ser Pro CysHis 675 680 685 Asn Gly Gly Thr Cys Glu Asp Gly Ile Ala Gly Phe Thr CysArg Cys 690 695 700 Pro Glu Gly Tyr His Asp Pro Thr Cys Leu Ser Glu ValAsn Glu Cys 705 710 715 720 Asn Ser Asn Pro Cys Ile His Gly Ala Cys ArgAsp Gly Leu Asn Gly 725 730 735 Tyr Lys Cys Asp Cys Ala Pro Gly Trp SerGly Thr Asn Cys Asp Ile 740 745 750 Asn Asn Asn Glu Cys Glu Ser Asn ProCys Val Asn Gly Gly Thr Cys 755 760 765 Lys Asp Met Thr Ser Gly Tyr ValCys Thr Cys Arg Glu Gly Phe Ser 770 775 780 Gly Pro Asn Cys Gln Thr AsnIle Asn Glu Cys Ala Ser Asn Pro Cys 785 790 795 800 Leu Asn Gln Gly ThrCys Ile Asp Asp Val Ala Gly Tyr Lys Cys Asn 805 810 815 Cys Pro Leu ProTyr Thr Gly Ala Thr Cys Glu Val Val Leu Ala Pro 820 825 830 Cys Ala ThrSer Pro Cys Lys Asn Ser Gly Val Cys Lys Glu Ser Glu 835 840 845 Asp TyrGlu Ser Phe Ser Cys Val Cys Pro Thr Gly Trp Gln Gly Gln 850 855 860 ThrCys Glu Ile Asp Ile Asn Glu Cys Val Lys Ser Pro Cys Arg His 865 870 875880 Gly Ala Ser Cys Gln Asn Thr Asn Gly Ser Tyr Arg Cys Leu Cys Gln 885890 895 Ala Gly Tyr Thr Gly Arg Asn Cys Glu Ser Asp Ile Asp Asp Cys Arg900 905 910 Pro Asn Pro Cys His Asn Gly Gly Ser Cys Thr Asp Gly Val AsnAla 915 920 925 Ala Phe Cys Asp Cys Leu Pro Gly Phe Gln Gly Ala Phe CysGlu Glu 930 935 940 Asp Ile Asn Glu Cys Ala Thr Asn Pro Cys Gln Asn GlyAla Asn Cys 945 950 955 960 Thr Asp Cys Val Asp Ser Tyr Thr Cys Thr CysPro Thr Gly Phe Asn 965 970 975 Gly Ile His Cys Glu Asn Asn Thr Pro AspCys Thr Glu Ser Ser Cys 980 985 990 Phe Asn Gly Gly Thr Cys Val Asp GlyIle Asn Ser Phe Thr Cys Leu 995 1000 1005 Cys Pro Pro Gly Phe Thr GlySer Tyr Cys Gln Tyr Asp Val Asn Glu 1010 1015 1020 Cys Asp Ser Arg ProCys Leu His Gly Gly Thr Cys Gln Asp Ser Tyr 1025 1030 1035 1040 Gly ThrTyr Lys Cys Thr Cys Pro Gln Gly Tyr Thr Gly Leu Asn Cys 1045 1050 1055Gln Asn Leu Val Arg Trp Cys Asp Ser Ala Pro Cys Lys Asn Gly Gly 10601065 1070 Lys Cys Trp Gln Thr Asn Thr Gln Tyr His Cys Glu Cys Arg SerGly 1075 1080 1085 Trp Thr Gly Phe Asn Cys Asp Val Leu Ser Val Ser CysGlu Val Ala 1090 1095 1100 Ala Gln Lys Arg Gly Ile Asp Val Thr Leu LeuCys Gln His Gly Gly 1105 1110 1115 1120 Leu Cys Val Asp Glu Glu Asp LysHis Tyr Cys His Cys Gln Ala Gly 1125 1130 1135 Tyr Thr Gly Ser Tyr CysGlu Asp Glu Val Asp Glu Cys Ser Pro Asn 1140 1145 1150 Pro Cys Gln AsnGly Ala Thr Cys Thr Asp Tyr Leu Gly Gly Phe Ser 1155 1160 1165 Cys LysCys Val Ala Gly Tyr His Gly Ser Asn Cys Ser Glu Glu Ile 1170 1175 1180Asn Glu Cys Leu Ser Gln Pro Cys Gln Asn Gly Gly Thr Cys Ile Asp 11851190 1195 1200 Leu Thr Asn Thr Tyr Lys Cys Ser Cys Pro Arg Gly Thr GlnGly Val 1205 1210 1215 His Cys Glu Ile Asn Val Asp Asp Cys His Pro ProLeu Asp Pro Ala 1220 1225 1230 Ser Arg Ser Pro Lys Cys Phe Asn Asn GlyThr Cys Val Asp Gln Val 1235 1240 1245 Gly Gly Tyr Thr Cys Thr Cys ProPro Gly Phe Val Gly Glu Arg Cys 1250 1255 1260 Glu Gly Asp Val Asn GluCys Leu Ser Asn Pro Cys Asp Pro Arg Gly 1265 1270 1275 1280 Thr Gln AsnCys Val Gln Arg Val Asn Asp Phe His Cys Glu Cys Arg 1285 1290 1295 AlaGly His Thr Gly Arg Arg Cys Glu Ser Val Ile Asn Gly Cys Arg 1300 13051310 Gly Lys Pro Cys Arg Asn Gly Gly Val Cys Ala Val Ala Ser Asn Thr1315 1320 1325 Ala Arg Gly Phe Ile Cys Arg Cys Pro Ala Arg Phe Glu GlyAla Thr 1330 1335 1340 Cys Glu Asn Asp Ala Arg Thr Cys Gly Ser Leu ArgCys Leu Asn Gly 1345 1350 1355 1360 Gly Thr Cys Ile Ser Gly Pro Arg SerPro Thr Cys Leu Cys Leu Gly 1365 1370 1375 Ser Phe Thr Gly Pro Glu CysGln Phe Pro Ala Ser Ser Pro Cys Val 1380 1385 1390 Gly Ser Asn Pro CysTyr Asn Gln Gly Thr Cys Glu Pro Thr Ser Glu 1395 1400 1405 Ser Pro PheTyr Arg Cys Leu Cys Pro Ala Lys Phe Asn Gly Leu Leu 1410 1415 1420 CysHis Ile Leu Asp Tyr Ser Phe Thr Gly Ala Ala Gly Arg Asp Ile 1425 14301435 1440 Pro Pro Pro Gln Ile Glu Glu Ala Cys Glu Leu Pro Glu Cys GlnGlu 1445 1450 1455 Asp Ala Gly Asn Lys Val Cys Asn Leu Gln Cys Asn AsnHis Ala Cys 1460 1465 1470 Gly Trp Asp Gly Gly Asp Cys Ser Leu Asn PheAsn Asp Pro Trp Lys 1475 1480 1485 Asn Cys Thr Gln Ser Leu Gln Cys TrpLys Tyr Phe Ser Asp Gly His 1490 1495 1500 Cys Asp Ser Gln Cys Asn SerAla Gly Cys Leu Phe Asp Gly Phe Asp 1505 1510 1515 1520 Cys Gln Leu ThrGlu Gly Gln Cys Asn Pro Leu Tyr Asp Gln Tyr Cys 1525 1530 1535 Lys AspHis Phe Ser Asp Gly His Cys Asp Gln Gly Cys Asn Ser Ala 1540 1545 1550Glu Cys Glu Trp Asp Gly Leu Asp Cys Ala Glu His Val Pro Glu Arg 15551560 1565 Leu Ala Ala Gly Thr Leu Val Leu Val Val Leu Leu Pro Pro AspGln 1570 1575 1580 Leu Arg Asn Asn Ser Phe His Phe Leu Arg Asp Val SerHis Val Leu 1585 1590 1595 1600 His Thr Asn Val Val Phe Lys Arg Asp AlaGln Gly Gln Gln Met Ile 1605 1610 1615 Phe Pro Tyr Tyr Gly Arg Glu GluGlu Leu Arg Lys His Pro Ile Lys 1620 1625 1630 Arg Ser Ala Val Gly TrpAla Thr Thr Ser Leu Leu Pro Gly Thr Asn 1635 1640 1645 Gly Gly Arg GlnArg Arg Glu Leu Asp Pro Met Asp Ile His Gly Ser 1650 1655 1660 Ile ValTyr Leu Glu Ile Asp Asn Arg Gln Cys Val Gln Ser Ser Ser 1665 1670 16751680 Gln Cys Phe Gln Ser Ala Thr Asp Val Ala Ala Phe Leu Gly Ala Leu1685 1690 1695 Ala Ser Leu Gly Ser Leu Asn Ile Pro Tyr Lys Ile Glu AlaVal Lys 1700 1705 1710 Ser Glu Thr Val Glu Pro Pro Leu Pro Ser Gln LeuHis Leu Met Tyr 1715 1720 1725 Val Ala Ala Ala Ala Phe Val Leu Leu PhePhe Val Gly Cys Gly Val 1730 1735 1740 Leu Leu Ser Arg Lys Arg Arg ArgGln His Gly Gln Leu Trp Phe Pro 1745 1750 1755 1760 Glu Gly Phe Lys ValSer Glu Ala Ser Lys Lys Lys Arg Arg Glu Pro 1765 1770 1775 Leu Gly GluAsp Ser Val Gly Leu Lys Pro Leu Lys Asn Ala Ser Asp 1780 1785 1790 GlyAla Leu Met Asp Asp Asn Gln Asn Glu Trp Gly Asp Glu Asp Leu 1795 18001805 Glu Thr Lys Lys Phe Arg Phe Glu Glu Pro Val Val Leu Pro Asp Leu1810 1815 1820 Asp Asp Gln Thr Asp His Arg Gln Trp Thr Gln Gln His LeuAsp Ala 1825 1830 1835 1840 Ala Asp Leu Arg Val Ser Ala Met Ala Pro ThrPro Pro Gln Gly Glu 1845 1850 1855 Val Asp Ala Asp Cys Met Asp Val AsnVal Arg Gly Pro Asp Gly Phe 1860 1865 1870 Thr Pro Leu Met Ile Ala SerCys Ser Gly Gly Gly Leu Glu Thr Gly 1875 1880 1885 Asn Ser Glu Glu GluGlu Asp Ala Pro Ala Val Ile Ser Asp Phe Ile 1890 1895 1900 Tyr Gln GlyAla Ser Leu His Asn Gln Thr Asp Arg Thr Gly Glu Thr 1905 1910 1915 1920Ala Leu His Leu Ala Ala Arg Tyr Ser Arg Ser Asp Ala Ala Lys Arg 19251930 1935 Leu Leu Glu Ala Ser Ala Asp Ala Asn Ile Gln Asp Asn Met GlyArg 1940 1945 1950 Thr Pro Leu His Ala Ala Val Ser Ala Asp Ala Gln GlyVal Phe Gln 1955 1960 1965 Ile Leu Leu Arg Asn Arg Ala Thr Asp Leu AspAla Arg Met His Asp 1970 1975 1980 Gly Thr Thr Pro Leu Ile Leu Ala AlaArg Leu Ala Val Glu Gly Met 1985 1990 1995 2000 Leu Glu Asp Leu Ile AsnSer His Ala Asp Val Asn Ala Val Asp Asp 2005 2010 2015 Leu Gly Lys SerAla Leu His Trp Ala Ala Ala Val Asn Asn Val Asp 2020 2025 2030 Ala AlaVal Val Leu Leu Lys Asn Gly Ala Asn Lys Asp Met Gln Asn 2035 2040 2045Asn Lys Glu Glu Thr Pro Leu Phe Leu Ala Ala Arg Glu Gly Ser Tyr 20502055 2060 Glu Thr Ala Lys Val Leu Leu Asp His Phe Ala Asn Arg Asp IleThr 2065 2070 2075 2080 Asp His Met Asp Arg Leu Pro Arg Asp Ile Ala GlnGlu Arg Met His 2085 2090 2095 His Asp Ile Val Arg Leu Leu Asp Glu TyrAsn Leu Val Arg Ser Pro 2100 2105 2110 Gln Leu His Gly Thr Ala Leu GlyGly Thr Pro Thr Leu Ser Pro Thr 2115 2120 2125 Leu Cys Ser Pro Asn GlyTyr Leu Gly Asn Leu Lys Ser Ala Thr Gln 2130 2135 2140 Gly Lys Lys AlaArg Lys Pro Ser Thr Lys Gly Leu Ala Cys Ser Ser 2145 2150 2155 2160 LysGlu Ala Lys Asp Leu Lys Ala Arg Arg Lys Lys Ser Gln Asp Gly 2165 21702175 Lys Gly Cys Leu Leu Asp Ser Ser Ser Met Leu Ser Pro Val Asp Ser2180 2185 2190 Leu Glu Ser Pro His Gly Tyr Leu Ser Asp Val Ala Ser ProPro Leu 2195 2200 2205 Leu Pro Ser Pro Phe Gln Gln Ser Pro Ser Met ProLeu Ser His Leu 2210 2215 2220 Pro Gly Met Pro Asp Thr His Leu Gly IleSer His Leu Asn Val Ala 2225 2230 2235 2240 Ala Lys Pro Glu Met Ala AlaLeu Ala Gly Gly Ser Arg Leu Ala Phe 2245 2250 2255 Glu Pro Pro Pro ProArg Leu Ser His Leu Pro Val Ala Ser Ser Ala 2260 2265 2270 Ser Thr ValLeu Ser Thr Asn Gly Thr Gly Ala Met Asn Phe Thr Val 2275 2280 2285 GlyAla Pro Ala Ser Leu Asn Gly Gln Cys Glu Trp Leu Pro Arg Leu 2290 22952300 Gln Asn Gly Met Val Pro Ser Gln Tyr Asn Pro Leu Arg Pro Gly Val2305 2310 2315 2320 Thr Pro Gly Thr Leu Ser Thr Gln Ala Ala Gly Leu GlnHis Gly Met 2325 2330 2335 Met Gly Pro Ile His Ser Ser Leu Ser Thr AsnThr Leu Ser Pro Ile 2340 2345 2350 Ile Tyr Gln Gly Leu Pro Asn Thr ArgLeu Ala Thr Gln Pro His Leu 2355 2360 2365 Val Gln Thr Gln Gln Val GlnPro Gln Asn Leu Gln Ile Gln Pro Gln 2370 2375 2380 Asn Leu Gln Pro ProSer Gln Pro His Leu Ser Val Ser Ser Ala Ala 2385 2390 2395 2400 Asn GlyHis Leu Gly Arg Ser Phe Leu Ser Gly Glu Pro Ser Gln Ala 2405 2410 2415Asp Val Gln Pro Leu Gly Pro Ser Ser Leu Pro Val His Thr Ile Leu 24202425 2430 Pro Gln Glu Ser Gln Ala Leu Pro Thr Ser Leu Pro Ser Ser MetVal 2435 2440 2445 Pro Pro Met Thr Thr Thr Gln Phe Leu Thr Pro Pro SerGln His Ser 2450 2455 2460 Tyr Ser Ser Ser Pro Val Asp Asn Thr Pro SerHis Gln Leu Gln Val 2465 2470 2475 2480 Pro Glu His Pro Phe Leu Thr ProSer Pro Glu Ser Pro Asp Gln Trp 2485 2490 2495 Ser Ser Ser Ser Arg HisSer Asn Ile Ser Asp Trp Ser Glu Gly Ile 2500 2505 2510 Ser Ser Pro ProThr Ser Met Pro Ser Gln Ile Thr His Ile Pro Glu 2515 2520 2525 Ala PheLys 2530 30 853 PRT Homo sapiens 30 Tyr Phe Ser Leu Phe Arg Ser Ile GlnLeu Phe Ala Asp Cys Lys Lys 1 5 10 15 Met Phe Leu Trp Leu Phe Leu IleLeu Ser Ala Leu Ile Ser Ser Thr 20 25 30 Asn Ala Asp Ser Asp Ile Ser ValGlu Ile Cys Asn Val Cys Ser Cys 35 40 45 Val Ser Val Glu Asn Val Leu TyrVal Asn Cys Glu Lys Val Ser Val 50 55 60 Tyr Arg Pro Asn Gln Leu Lys ProPro Trp Ser Asn Phe Tyr His Leu 65 70 75 80 Asn Phe Gln Asn Asn Phe LeuAsn Ile Leu Tyr Pro Asn Thr Phe Leu 85 90 95 Asn Phe Ser His Ala Val SerLeu His Leu Gly Asn Asn Lys Leu Gln 100 105 110 Asn Ile Glu Gly Gly AlaPhe Leu Gly Leu Ser Ala Leu Lys Gln Leu 115 120 125 His Leu Asn Asn AsnGlu Leu Lys Ile Leu Arg Ala Asp Thr Phe Leu 130 135 140 Gly Ile Glu AsnLeu Glu Tyr Leu Gln Ala Asp Tyr Asn Leu Ile Lys 145 150 155 160 Tyr IleGlu Arg Gly Ala Phe Asn Lys Leu His Lys Leu Lys Val Leu 165 170 175 IleLeu Asn Asp Asn Leu Ile Ser Phe Leu Pro Asp Asn Ile Phe Arg 180 185 190Phe Ala Ser Leu Thr His Leu Asp Ile Arg Gly Asn Arg Ile Gln Lys 195 200205 Leu Pro Tyr Ile Gly Val Leu Glu His Ile Gly Arg Val Val Glu Leu 210215 220 Gln Leu Glu Asp Asn Pro Trp Asn Cys Ser Cys Asp Leu Leu Pro Leu225 230 235 240 Lys Ala Trp Leu Glu Asn Met Pro Tyr Asn Ile Tyr Ile GlyGlu Ala 245 250 255 Ile Cys Glu Thr Pro Ser Asp Leu Tyr Gly Arg Leu LeuLys Glu Thr 260 265 270 Asn Lys Gln Glu Leu Cys Pro Met Gly Thr Gly SerAsp Phe Asp Val 275 280 285 Arg Ile Leu Pro Pro Ser Gln Leu Glu Asn GlyTyr Thr Thr Pro Asn 290 295 300 Gly His Thr Thr Gln Thr Ser Leu His ArgLeu Val Thr Lys Pro Pro 305 310 315 320 Lys Thr Thr Asn Pro Ser Lys IleSer Gly Ile Val Ala Gly Lys Ala 325 330 335 Leu Ser Asn Arg Asn Leu SerGln Ile Val Ser Tyr Gln Thr Arg Val 340 345 350 Pro Pro Leu Thr Pro CysPro Ala Pro Cys Phe Cys Lys Thr His Pro 355 360 365 Ser Asp Leu Gly LeuSer Val Asn Cys Gln Glu Lys Asn Ile Gln Ser 370 375 380 Met Ser Glu LeuIle Pro Lys Pro Leu Asn Ala Lys Lys Leu His Val 385 390 395 400 Asn GlyAsn Ser Ile Lys Asp Val Asp Val Ser Asp Phe Thr Asp Phe 405 410 415 GluGly Leu Asp Leu Leu His Leu Gly Ser Asn Gln Ile Thr Val Ile 420 425 430Lys Gly Asp Val Phe His Asn Leu Thr Asn Leu Arg Arg Leu Tyr Leu 435 440445 Asn Gly Asn Gln Ile Glu Arg Leu Tyr Pro Glu Ile Phe Ser Gly Leu 450455 460 His Asn Leu Gln Tyr Leu Tyr Leu Glu Tyr Asn Leu Ile Lys Glu Ile465 470 475 480 Ser Ala Gly Thr Phe Asp Ser Met Pro Asn Leu Gln Leu LeuTyr Leu 485 490 495 Asn Asn Asn Leu Leu Lys Ser Leu Pro Val Tyr Ile PheSer Gly Ala 500 505 510 Pro Leu Ala Arg Leu Asn Leu Arg Asn Asn Lys PheMet Tyr Leu Pro 515 520 525 Val Ser Gly Val Leu Asp Gln Leu Gln Ser LeuThr Gln Ile Asp Leu 530 535 540 Glu Gly Asn Pro Trp Asp Cys Thr Cys AspLeu Val Ala Leu Lys Leu 545 550 555 560 Trp Val Glu Lys Leu Ser Asp GlyIle Val Val Lys Glu Leu Lys Cys 565 570 575 Glu Thr Pro Val Gln Phe AlaAsn Ile Glu Leu Lys Ser Leu Lys Asn 580 585 590 Glu Ile Leu Cys Pro LysLeu Leu Asn Lys Pro Ser Ala Pro Phe Thr 595 600 605 Ser Pro Ala Pro AlaIle Thr Phe Thr Thr Pro Leu Gly Pro Ile Arg 610 615 620 Ser Pro Pro GlyGly Pro Val Pro Leu Ser Ile Leu Ile Leu Ser Ile 625 630 635 640 Leu ValVal Leu Ile Leu Thr Val Phe Val Ala Phe Cys Leu Leu Val 645 650 655 PheVal Leu Arg Arg Asn Lys Lys Pro Thr Val Lys His Glu Gly Leu 660 665 670Gly Asn Pro Asp Cys Gly Ser Met Gln Leu Gln Leu Arg Lys His Asp 675 680685 His Lys Thr Asn Lys Lys Asp Gly Leu Ser Thr Glu Ala Phe Ile Pro 690695 700 Gln Thr Ile Glu Gln Met Ser Lys Ser His Thr Cys Gly Leu Lys Glu705 710 715 720 Ser Glu Thr Gly Phe Met Phe Ser Asp Pro Pro Gly Gln LysVal Val 725 730 735 Met Arg Asn Val Ala Asp Lys Glu Lys Asp Leu Leu HisVal Asp Thr 740 745 750 Arg Lys Arg Leu Ser Thr Ile Asp Glu Leu Asp GluLeu Phe Pro Ser 755 760 765 Arg Asp Ser Asn Val Phe Ile Gln Asn Phe LeuGlu Ser Lys Lys Glu 770 775 780 Tyr Asn Ser Ile Gly Val Ser Gly Phe GluIle Arg Tyr Pro Glu Lys 785 790 795 800 Gln Pro Asp Lys Lys Ser Lys LysSer Leu Ile Gly Gly Asn His Ser 805 810 815 Lys Ile Val Val Glu Gln ArgLys Ser Glu Tyr Phe Glu Leu Lys Ala 820 825 830 Lys Leu Gln Ser Ser ProAsp Tyr Leu Gln Val Leu Glu Glu Gln Thr 835 840 845 Ala Leu Asn Lys Ile850 31 966 PRT Homo sapiens 31 Arg Arg Gly Ala Gln Gly Gly Lys Met HisThr Cys Cys Pro Pro Val 1 5 10 15 Thr Leu Glu Gln Asp Leu His Arg LysMet His Ser Trp Met Leu Gln 20 25 30 Thr Leu Ala Phe Ala Val Thr Ser LeuVal Leu Ser Cys Ala Glu Thr 35 40 45 Ile Asp Tyr Tyr Gly Glu Ile Cys AspAsn Ala Cys Pro Cys Glu Glu 50 55 60 Lys Asp Gly Ile Leu Thr Val Ser CysGlu Asn Arg Gly Ile Ile Ser 65 70 75 80 Leu Ser Glu Ile Ser Pro Pro ArgPhe Pro Ile Tyr His Leu Leu Leu 85 90 95 Ser Gly Asn Leu Leu Asn Arg LeuTyr Pro Asn Glu Phe Val Asn Tyr 100 105 110 Thr Gly Ala Ser Ile Leu HisLeu Gly Ser Asn Val Ile Gln Asp Ile 115 120 125 Glu Thr Gly Ala Phe HisGly Leu Arg Gly Leu Arg Arg Leu His Leu 130 135 140 Asn Asn Asn Lys LeuGlu Leu Leu Arg Asp Asp Thr Phe Leu Gly Leu 145 150 155 160 Glu Asn LeuGlu Tyr Leu Gln Val Asp Tyr Asn Tyr Ile Ser Val Ile 165 170 175 Glu ProAsn Ala Phe Gly Lys Leu His Leu Leu Gln Val Leu Ile Leu 180 185 190 AsnAsp Asn Leu Leu Ser Ser Leu Pro Asn Asn Leu Phe Arg Phe Val 195 200 205Pro Leu Thr His Leu Asp Leu Arg Gly Asn Arg Leu Lys Leu Leu Pro 210 215220 Tyr Val Gly Leu Leu Gln His Met Asp Lys Val Val Glu Leu Gln Leu 225230 235 240 Glu Glu Asn Pro Trp Asn Cys Ser Cys Glu Leu Ile Ser Leu LysAsp 245 250 255 Trp Leu Asp Ser Ile Ser Tyr Ser Ala Leu Val Gly Asp ValVal Cys 260 265 270 Glu Thr Pro Phe Arg Leu His Gly Arg Asp Leu Asp GluVal Ser Lys 275 280 285 Gln Glu Leu Cys Pro Arg Arg Leu Ile Ser Asp TyrGlu Met Arg Pro 290 295 300 Gln Thr Pro Leu Ser Thr Thr Gly Tyr Leu HisThr Thr Pro Ala Ser 305 310 315 320 Val Asn Ser Val Ala Thr Ser Ser SerAla Val Tyr Lys Pro Pro Leu 325 330 335 Lys Pro Pro Lys Gly Thr Arg GlnPro Asn Lys Pro Arg Val Arg Pro 340 345 350 Thr Ser Arg Gln Pro Ser LysAsp Leu Gly Tyr Ser Asn Tyr Gly Pro 355 360 365 Ser Ile Ala Tyr Gln ThrLys Ser Pro Val Pro Leu Glu Cys Pro Thr 370 375 380 Ala Cys Ser Cys AsnLeu Gln Ile Ser Asp Leu Gly Leu Asn Val Asn 385 390 395 400 Cys Gln GluArg Lys Ile Glu Ser Ile Ala Glu Leu Gln Pro Lys Pro 405 410 415 Tyr AsnPro Lys Lys Met Tyr Leu Thr Glu Asn Tyr Ile Ala Val Val 420 425 430 ArgArg Thr Asp Phe Leu Glu Ala Thr Gly Leu Asp Leu Leu His Leu 435 440 445Gly Asn Asn Arg Ile Ser Met Ile Gln Asp Arg Ala Phe Gly Asp Leu 450 455460 Thr Asn Leu Arg Arg Leu Tyr Leu Asn Gly Asn Arg Ile Glu Arg Leu 465470 475 480 Ser Pro Glu Leu Phe Tyr Gly Leu Gln Ser Leu Gln Tyr Leu PheLeu 485 490 495 Gln Tyr Asn Leu Ile Arg Glu Ile Gln Ser Gly Thr Phe AspPro Val 500 505 510 Pro Asn Leu Gln Leu Leu Phe Leu Asn Asn Asn Leu LeuGln Ala Met 515 520 525 Pro Ser Gly Val Phe Ser Gly Leu Thr Leu Leu ArgLeu Asn Leu Arg 530 535 540 Ser Asn His Phe Thr Ser Leu Pro Val Ser GlyVal Leu Asp Gln Leu 545 550 555 560 Lys Ser Leu Ile Gln Ile Asp Leu HisAsp Asn Pro Trp Asp Cys Thr 565 570 575 Cys Asp Ile Val Gly Met Lys LeuTrp Val Glu Gln Leu Lys Val Gly 580 585 590 Val Leu Val Asp Glu Val IleCys Lys Ala Pro Lys Lys Phe Ala Glu 595 600 605 Thr Asp Met Arg Ser IleLys Ser Glu Leu Leu Cys Pro Asp Tyr Ser 610 615 620 Asp Val Val Val SerThr Pro Thr Pro Ser Ser Ile Gln Val Pro Ala 625 630 635 640 Arg Thr SerAla Val Thr Pro Ala Val Arg Leu Asn Ser Thr Gly Ala 645 650 655 Pro AlaSer Leu Gly Ala Gly Gly Gly Ala Ser Ser Val Pro Leu Ser 660 665 670 ValLeu Ile Leu Ser Leu Leu Leu Val Phe Ile Met Ser Val Phe Val 675 680 685Ala Ala Gly Leu Phe Val Leu Val Met Lys Arg Arg Lys Lys Asn Gln 690 695700 Ser Asp His Thr Ser Thr Asn Asn Ser Asp Val Ser Ser Phe Asn Met 705710 715 720 Gln Tyr Ser Val Tyr Gly Gly Gly Gly Gly Thr Gly Gly His ProHis 725 730 735 Ala His Val His His Arg Gly Pro Ala Leu Pro Lys Val LysThr Pro 740 745 750 Ala Gly His Val Tyr Glu Tyr Ile Pro His Pro Leu GlyHis Met Cys 755 760 765 Lys Asn Pro Ile Tyr Arg Ser Arg Glu Gly Asn SerVal Glu Asp Tyr 770 775 780 Lys Asp Leu His Glu Leu Lys Val Thr Tyr SerSer Asn His His Leu 785 790 795 800 Gln Gln Gln Gln Gln Pro Pro Pro ProPro Gln Gln Pro Gln Gln Gln 805 810 815 Pro Pro Pro Gln Leu Gln Leu GlnPro Gly Glu Glu Glu Arg Arg Glu 820 825 830 Ser His His Leu Arg Ser ProAla Tyr Ser Val Ser Thr Ile Glu Pro 835 840 845 Arg Glu Asp Leu Leu SerPro Val Gln Asp Ala Asp Arg Phe Tyr Arg 850 855 860 Gly Ile Leu Glu ProAsp Lys His Cys Ser Thr Thr Pro Ala Gly Asn 865 870 875 880 Ser Leu ProGlu Tyr Pro Lys Phe Pro Cys Ser Pro Ala Ala Tyr Thr 885 890 895 Phe SerPro Asn Tyr Asp Leu Arg Arg Pro His Gln Tyr Leu His Pro 900 905 910 GlyAla Gly Asp Ser Arg Leu Arg Glu Pro Val Leu Tyr Ser Pro Pro 915 920 925Ser Ala Val Phe Val Glu Pro Asn Arg Asn Glu Tyr Leu Glu Leu Lys 930 935940 Ala Lys Leu Asn Val Glu Pro Asp Tyr Leu Glu Val Leu Glu Lys Gln 945950 955 960 Thr Thr Phe Ser Gln Phe 965 32 845 PRT Homo sapiens 32 MetLeu Ser Gly Val Trp Phe Leu Ser Val Leu Thr Val Ala Gly Ile 1 5 10 15Leu Gln Thr Glu Ser Arg Lys Thr Ala Lys Asp Ile Cys Lys Ile Arg 20 25 30Cys Leu Cys Glu Glu Lys Glu Asn Val Leu Asn Ile Asn Cys Glu Asn 35 40 45Lys Gly Phe Thr Thr Val Ser Leu Leu Gln Pro Pro Gln Tyr Arg Ile 50 55 60Tyr Gln Leu Phe Leu Asn Gly Asn Leu Leu Thr Arg Leu Tyr Pro Asn 65 70 7580 Glu Phe Val Asn Tyr Ser Asn Ala Val Thr Leu His Leu Gly Asn Asn 85 9095 Gly Leu Gln Glu Ile Arg Thr Gly Ala Phe Ser Gly Leu Lys Thr Leu 100105 110 Lys Arg Leu His Leu Asn Asn Asn Lys Leu Glu Ile Leu Arg Glu Asp115 120 125 Thr Phe Leu Gly Leu Glu Ser Leu Glu Tyr Leu Gln Ala Asp TyrAsn 130 135 140 Tyr Ile Ser Ala Ile Glu Ala Gly Ala Phe Ser Lys Leu AsnLys Leu 145 150 155 160 Lys Val Leu Ile Leu Asn Asp Asn Leu Leu Leu SerLeu Pro Ser Asn 165 170 175 Val Phe Arg Phe Val Leu Leu Thr His Leu AspLeu Arg Gly Asn Arg 180 185 190 Leu Lys Val Met Pro Phe Ala Gly Val LeuGlu His Ile Gly Gly Ile 195 200 205 Met Glu Ile Gln Leu Glu Glu Asn ProTrp Asn Cys Thr Cys Asp Leu 210 215 220 Leu Pro Leu Lys Ala Trp Leu AspThr Ile Thr Val Phe Val Gly Glu 225 230 235 240 Ile Val Cys Glu Thr ProPhe Arg Leu His Gly Lys Asp Val Thr Gln 245 250 255 Leu Thr Arg Gln AspLeu Cys Pro Arg Lys Ser Ala Ser Asp Ser Ser 260 265 270 Gln Arg Gly SerHis Ala Asp Thr His Val Gln Arg Leu Ser Pro Thr 275 280 285 Met Asn ProAla Leu Asn Pro Thr Arg Ala Pro Lys Ala Ser Arg Pro 290 295 300 Pro LysMet Arg Asn Arg Pro Thr Pro Arg Val Thr Val Ser Lys Asp 305 310 315 320Arg Gln Ser Phe Gly Pro Ile Met Val Tyr Gln Thr Lys Ser Pro Val 325 330335 Pro Leu Thr Cys Pro Ser Ser Cys Val Cys Thr Ser Gln Ser Ser Asp 340345 350 Asn Gly Leu Asn Val Asn Cys Gln Glu Arg Lys Phe Thr Asn Ile Ser355 360 365 Asp Leu Gln Pro Lys Pro Thr Ser Pro Lys Lys Leu Tyr Leu ThrGly 370 375 380 Asn Tyr Leu Gln Thr Val Tyr Lys Asn Asp Leu Leu Glu TyrSer Ser 385 390 395 400 Leu Asp Leu Leu His Leu Gly Asn Asn Arg Ile AlaVal Ile Gln Glu 405 410 415 Gly Ala Phe Thr Asn Leu Thr Ser Leu Arg ArgLeu Tyr Leu Asn Gly 420 425 430 Asn Tyr Leu Glu Val Leu Tyr Pro Ser MetPhe Asp Gly Leu Gln Ser 435 440 445 Leu Gln Tyr Leu Tyr Leu Glu Tyr AsnVal Ile Lys Glu Ile Lys Pro 450 455 460 Leu Thr Phe Asp Ala Leu Ile AsnLeu Gln Leu Leu Phe Leu Asn Asn 465 470 475 480 Asn Leu Leu Arg Ser LeuPro Asp Asn Ile Phe Gly Gly Thr Ala Leu 485 490 495 Thr Arg Leu Asn LeuArg Asn Asn His Phe Ser His Leu Pro Val Lys 500 505 510 Gly Val Leu AspGln Leu Pro Ala Phe Ile Gln Ile Asp Leu Gln Glu 515 520 525 Asn Pro TrpAsp Cys Thr Cys Asp Ile Met Gly Leu Lys Asp Trp Thr 530 535 540 Glu HisAla Asn Ser Pro Val Ile Ile Asn Glu Val Thr Cys Glu Ser 545 550 555 560Pro Ala Lys His Ala Gly Glu Ile Leu Lys Phe Leu Gly Arg Glu Ala 565 570575 Ile Cys Pro Asp Ser Pro Asn Leu Ser Asp Gly Thr Val Leu Ser Met 580585 590 Asn His Asn Thr Asp Thr Pro Arg Ser Leu Ser Val Ser Pro Ser Ser595 600 605 Tyr Pro Glu Leu His Thr Glu Val Pro Leu Ser Val Leu Ile LeuGly 610 615 620 Leu Leu Val Val Phe Ile Leu Ser Val Cys Phe Gly Ala GlyLeu Phe 625 630 635 640 Val Phe Val Leu Lys Arg Arg Lys Gly Val Pro SerVal Pro Arg Asn 645 650 655 Thr Asn Asn Leu Asp Val Ser Ser Phe Gln LeuGln Tyr Gly Ser Tyr 660 665 670 Asn Thr Glu Thr His Asp Lys Thr Asp GlyHis Val Tyr Asn Tyr Ile 675 680 685 Pro Pro Pro Val Gly Gln Met Cys GlnAsn Pro Ile Tyr Met Gln Lys 690 695 700 Glu Gly Asp Pro Val Ala Tyr TyrArg Asn Leu Gln Glu Phe Ser Tyr 705 710 715 720 Ser Asn Leu Glu Glu LysLys Glu Glu Pro Ala Thr Pro Ala Tyr Thr 725 730 735 Ile Ser Ala Thr GluLeu Leu Glu Lys Gln Ala Thr Pro Arg Glu Pro 740 745 750 Glu Leu Leu TyrGln Asn Ile Ala Glu Arg Val Lys Glu Leu Pro Ser 755 760 765 Ala Gly LeuVal His Tyr Asn Phe Cys Thr Leu Pro Lys Arg Gln Phe 770 775 780 Ala ProSer Tyr Glu Ser Arg Arg Gln Asn Gln Asp Arg Ile Asn Lys 785 790 795 800Thr Val Leu Tyr Gly Thr Pro Arg Lys Cys Phe Val Gly Gln Ser Lys 805 810815 Pro Asn His Pro Leu Leu Gln Ala Lys Pro Gln Ser Glu Pro Asp Tyr 820825 830 Leu Glu Val Leu Glu Lys Gln Thr Ala Ile Ser Gln Leu 835 840 84533 572 PRT Homo sapiens 33 His Arg Arg Cys Leu Lys Met Leu Ser Gly ValTrp Phe Leu Ser Val 1 5 10 15 Leu Thr Val Ala Gly Ile Leu Gln Thr GluSer Arg Lys Thr Ala Lys 20 25 30 Asp Ile Cys Lys Ile Arg Cys Leu Cys GluGlu Lys Glu Asn Val Leu 35 40 45 Asn Ile Asn Cys Glu Asn Lys Gly Phe ThrThr Val Ser Leu Leu Gln 50 55 60 Pro Pro Gln Tyr Arg Ile Tyr Gln Leu PheLeu Asn Gly Asn Leu Leu 65 70 75 80 Thr Arg Leu Tyr Pro Asn Glu Phe ValAsn Tyr Ser Asn Ala Val Thr 85 90 95 Leu His Leu Gly Asn Asn Gly Leu GlnGlu Ile Arg Thr Gly Ala Phe 100 105 110 Ser Gly Leu Lys Thr Leu Lys ArgLeu His Leu Asn Asn Asn Lys Leu 115 120 125 Glu Ile Leu Arg Glu Asp ThrPhe Leu Gly Leu Glu Ser Leu Glu Tyr 130 135 140 Leu Gln Ala Asp Tyr AsnTyr Ile Ser Ala Ile Glu Ala Gly Ala Phe 145 150 155 160 Ser Lys Leu AsnLys Leu Lys Val Leu Ile Leu Asn Asp Asn Leu Leu 165 170 175 Leu Ser LeuPro Ser Asn Val Phe Arg Phe Val Leu Leu Thr His Leu 180 185 190 Asp LeuArg Gly Asn Arg Leu Lys Val Met Pro Phe Ala Gly Val Leu 195 200 205 GluHis Ile Gly Gly Ile Met Glu Ile Gln Leu Glu Glu Asn Pro Trp 210 215 220Asn Cys Thr Cys Asp Leu Leu Pro Leu Lys Ala Trp Leu Asp Thr Ile 225 230235 240 Thr Val Phe Val Gly Glu Ile Val Cys Glu Thr Pro Phe Arg Leu His245 250 255 Gly Lys Asp Val Thr Gln Leu Thr Arg Gln Asp Leu Cys Pro ArgLys 260 265 270 Ser Ala Ser Asp Ser Ser Gln Arg Gly Ser His Ala Asp ThrHis Val 275 280 285 Gln Arg Leu Ser Pro Thr Met Asn Pro Ala Leu Asn ProThr Arg Ala 290 295 300 Pro Lys Ala Ser Arg Pro Pro Lys Met Arg Asn ArgPro Thr Pro Arg 305 310 315 320 Val Thr Val Ser Lys Asp Arg Gln Ser PheGly Pro Ile Met Val Tyr 325 330 335 Gln Thr Lys Ser Pro Val Pro Leu ThrCys Pro Ser Ser Cys Val Cys 340 345 350 Thr Ser Gln Ser Ser Asp Asn GlyLeu Asn Val Asn Cys Gln Glu Arg 355 360 365 Lys Phe Thr Asn Ile Ser AspLeu Gln Pro Lys Pro Thr Ser Pro Lys 370 375 380 Lys Leu Tyr Leu Thr GlyAsn Tyr Leu Gln Thr Val Tyr Lys Asn Asp 385 390 395 400 Leu Leu Glu TyrSer Ser Leu Asp Leu Leu His Leu Gly Asn Asn Arg 405 410 415 Ile Ala ValIle Gln Glu Gly Ala Phe Thr Asn Leu Thr Ser Leu Arg 420 425 430 Arg LeuTyr Leu Asn Gly Asn Tyr Leu Glu Val Leu Tyr Pro Ser Met 435 440 445 PheAsp Gly Leu Gln Ser Leu Gln Tyr Leu Tyr Leu Glu Tyr Asn Val 450 455 460Ile Lys Glu Ile Lys Pro Leu Thr Phe Asp Ala Leu Ile Asn Leu Gln 465 470475 480 Leu Leu Phe Leu Asn Asn Asn Leu Leu Arg Ser Leu Pro Asp Asn Ile485 490 495 Phe Gly Gly Thr Ala Leu Thr Arg Leu Asn Leu Arg Asn Asn HisPhe 500 505 510 Ser His Leu Pro Val Lys Gly Val Leu Asp Gln Leu Pro AlaPhe Ile 515 520 525 Gln Ile Asp Leu Gln Glu Asn Pro Trp Asp Cys Thr CysAsp Ile Met 530 535 540 Gly Leu Lys Asp Trp Thr Glu His Ala Asn Ser ProVal Ile Ile Asn 545 550 555 560 Glu Val Thr Cys Glu Ser Pro Ala Lys HisAla Gly 565 570 34 977 PRT Homo sapiens 34 Met Lys Pro Ser Ile Ala GluMet Leu His Arg Gly Arg Met Leu Trp 1 5 10 15 Ile Ile Leu Leu Ser ThrIle Ala Leu Gly Trp Thr Thr Pro Ile Pro 20 25 30 Leu Ile Glu Asp Ser GluGlu Ile Asp Glu Pro Cys Phe Asp Pro Cys 35 40 45 Tyr Cys Glu Val Lys GluSer Leu Phe His Ile His Cys Asp Ser Lys 50 55 60 Gly Phe Thr Asn Ile SerGln Ile Thr Glu Phe Trp Ser Arg Pro Phe 65 70 75 80 Lys Leu Tyr Leu GlnArg Asn Ser Met Arg Lys Leu Tyr Thr Asn Ser 85 90 95 Phe Leu His Leu AsnAsn Ala Val Ser Ile Asn Leu Gly Asn Asn Ala 100 105 110 Leu Gln Asp IleGln Thr Gly Ala Phe Asn Gly Leu Lys Ile Leu Lys 115 120 125 Arg Leu TyrLeu His Glu Asn Lys Leu Asp Val Phe Arg Asn Asp Thr 130 135 140 Phe LeuGly Leu Glu Ser Leu Glu Tyr Leu Gln Ala Asp Tyr Asn Val 145 150 155 160Ile Lys Arg Ile Glu Ser Gly Ala Phe Arg Asn Leu Ser Lys Leu Arg 165 170175 Val Leu Ile Leu Asn Asp Asn Leu Ile Pro Met Leu Pro Thr Asn Leu 180185 190 Phe Lys Ala Val Ser Leu Thr His Leu Asp Leu Arg Gly Asn Arg Leu195 200 205 Lys Val Leu Phe Tyr Arg Gly Met Leu Asp His Ile Gly Arg SerLeu 210 215 220 Met Glu Leu Gln Leu Glu Glu Asn Pro Trp Asn Cys Thr CysGlu Ile 225 230 235 240 Val Gln Leu Lys Ser Trp Leu Glu Arg Ile Pro TyrThr Ala Leu Val 245 250 255 Gly Asp Ile Thr Cys Glu Thr Pro Phe His PheHis Gly Lys Asp Leu 260 265 270 Arg Glu Ile Arg Lys Thr Glu Leu Cys ProLeu Leu Ser Asp Ser Glu 275 280 285 Val Glu Ala Ser Leu Gly Ile Pro HisSer Ser Ser Ser Lys Glu Asn 290 295 300 Ala Trp Pro Thr Lys Pro Ser SerMet Leu Ser Ser Val His Phe Thr 305 310 315 320 Ala Ser Ser Val Glu TyrLys Ser Ser Asn Lys Gln Pro Lys Pro Thr 325 330 335 Lys Gln Pro Arg ThrPro Arg Pro Pro Ser Thr Ser Gln Ala Leu Tyr 340 345 350 Pro Gly Pro AsnGln Pro Pro Ile Ala Pro Tyr Gln Thr Arg Pro Pro 355 360 365 Ile Pro IleIle Cys Pro Thr Gly Cys Thr Cys Asn Leu His Ile Asn 370 375 380 Asp LeuGly Leu Thr Val Asn Cys Lys Glu Arg Gly Phe Asn Asn Ile 385 390 395 400Ser Glu Leu Leu Pro Arg Pro Leu Asn Ala Lys Lys Leu Tyr Leu Ser 405 410415 Ser Asn Leu Ile Gln Lys Ile Tyr Arg Ser Asp Phe Trp Asn Phe Ser 420425 430 Ser Leu Asp Leu Leu His Leu Gly Asn Asn Arg Ile Ser Tyr Val Gln435 440 445 Asp Gly Ala Phe Ile Asn Leu Pro Asn Leu Lys Ser Leu Phe LeuAsn 450 455 460 Gly Asn Asp Ile Glu Lys Leu Thr Pro Gly Met Phe Arg GlyLeu Gln 465 470 475 480 Ser Leu His Tyr Leu Tyr Phe Glu Phe Asn Val IleArg Glu Ile Gln 485 490 495 Pro Ala Ala Phe Ser Leu Met Pro Asn Leu LysLeu Leu Phe Leu Asn 500 505 510 Asn Asn Leu Leu Arg Thr Leu Pro Thr AspAla Phe Ala Gly Thr Ser 515 520 525 Leu Ala Arg Leu Asn Leu Arg Lys AsnTyr Phe Leu Tyr Leu Pro Val 530 535 540 Ala Gly Val Leu Glu His Leu AsnAla Ile Val Gln Ile Asp Leu Asn 545 550 555 560 Glu Asn Pro Trp Asp CysThr Cys Asp Leu Val Pro Phe Lys Gln Trp 565 570 575 Ile Glu Thr Ile SerSer Val Ser Val Val Gly Asp Val Leu Cys Arg 580 585 590 Ser Pro Glu AsnLeu Thr His Arg Asp Val Arg Thr Ile Glu Leu Glu 595 600 605 Val Leu CysPro Glu Met Leu His Val Ala Pro Ala Gly Glu Ser Pro 610 615 620 Ala GlnPro Gly Asp Ser His Leu Ile Gly Ala Pro Thr Ser Ala Ser 625 630 635 640Pro Tyr Glu Phe Ser Pro Pro Gly Gly Pro Val Pro Leu Ser Val Leu 645 650655 Ile Leu Ser Leu Leu Val Leu Phe Phe Ser Ala Val Phe Val Ala Ala 660665 670 Gly Leu Phe Ala Tyr Val Leu Arg Arg Arg Arg Lys Lys Leu Pro Phe675 680 685 Arg Ser Lys Arg Gln Glu Gly Val Asp Leu Thr Gly Ile Gln MetGln 690 695 700 Cys His Arg Leu Phe Glu Asp Gly Gly Gly Gly Gly Gly GlySer Gly 705 710 715 720 Gly Gly Gly Arg Pro Thr Leu Ser Ser Pro Glu LysAla Pro Pro Val 725 730 735 Gly His Val Tyr Glu Tyr Ile Pro His Pro ValThr Gln Met Cys Asn 740 745 750 Asn Pro Ile Tyr Lys Pro Arg Glu Glu GluGlu Val Ala Val Ser Ser 755 760 765 Ala Gln Glu Ala Gly Ser Ala Glu ArgGly Gly Pro Gly Thr Gln Pro 770 775 780 Pro Gly Met Gly Glu Ala Leu LeuGly Ser Glu Gln Phe Ala Glu Thr 785 790 795 800 Pro Lys Glu Asn His SerAsn Tyr Arg Thr Leu Leu Glu Lys Glu Lys 805 810 815 Glu Trp Ala Leu AlaVal Ser Ser Ser Gln Leu Asn Thr Ile Val Thr 820 825 830 Val Asn His HisHis Pro His His Pro Ala Val Gly Gly Val Ser Gly 835 840 845 Val Val GlyGly Thr Gly Gly Asp Leu Ala Gly Phe Arg His His Glu 850 855 860 Lys AsnGly Gly Val Val Leu Phe Pro Pro Gly Gly Gly Cys Gly Ser 865 870 875 880Gly Ser Met Leu Leu Asp Arg Glu Arg Pro Gln Pro Ala Pro Cys Thr 885 890895 Val Gly Phe Val Asp Cys Leu Tyr Gly Thr Val Pro Lys Leu Lys Glu 900905 910 Leu His Val His Pro Pro Gly Met Gln Tyr Pro Asp Leu Gln Gln Asp915 920 925 Ala Arg Leu Lys Glu Thr Leu Leu Phe Ser Ala Gly Lys Gly PheThr 930 935 940 Asp His Gln Thr Gln Lys Ser Asp Tyr Leu Glu Leu Arg AlaLys Leu 945 950 955 960 Gln Thr Lys Pro Asp Tyr Leu Glu Val Leu Glu LysThr Thr Tyr Arg 965 970 975 Phe 35 762 PRT Homo sapiens 35 Met Ala LeuPro Ala Leu Gly Leu Asp Pro Trp Ser Leu Leu Gly Leu 1 5 10 15 Phe LeuPhe Gln Leu Leu Gln Leu Leu Leu Pro Thr Thr Thr Ala Gly 20 25 30 Gly GlyGly Gln Gly Pro Met Pro Arg Val Arg Tyr Tyr Ala Gly Asp 35 40 45 Glu ArgArg Ala Leu Ser Phe Phe His Gln Lys Gly Leu Gln Asp Phe 50 55 60 Asp ThrLeu Leu Leu Ser Gly Asp Gly Asn Thr Leu Tyr Val Gly Ala 65 70 75 80 ArgGlu Ala Ile Leu Ala Leu Asp Ile Gln Asp Pro Gly Val Pro Arg 85 90 95 LeuLys Asn Met Ile Pro Trp Pro Ala Ser Asp Arg Lys Lys Ser Glu 100 105 110Cys Ala Phe Lys Lys Lys Ser Asn Glu Thr Gln Cys Phe Asn Phe Ile 115 120125 Arg Val Leu Val Ser Tyr Asn Val Thr His Leu Tyr Thr Cys Gly Thr 130135 140 Phe Ala Phe Ser Pro Ala Cys Thr Phe Ile Glu Leu Gln Asp Ser Tyr145 150 155 160 Leu Leu Pro Ile Ser Glu Asp Lys Val Met Glu Gly Lys GlyGln Ser 165 170 175 Pro Phe Asp Pro Ala His Lys His Thr Ala Val Leu ValAsp Gly Met 180 185 190 Leu Tyr Ser Gly Thr Met Asn Asn Phe Leu Gly SerGlu Pro Ile Leu 195 200 205 Met Arg Thr Leu Gly Ser Gln Pro Val Leu LysThr Asp Asn Phe Leu 210 215 220 Arg Trp Leu His His Asp Ala Ser Phe ValAla Ala Ile Pro Ser Thr 225 230 235 240 Gln Val Val Tyr Phe Phe Phe GluGlu Thr Ala Ser Glu Phe Asp Phe 245 250 255 Phe Glu Arg Leu His Thr SerArg Val Ala Arg Val Cys Lys Asn Asp 260 265 270 Val Gly Gly Glu Lys LeuLeu Gln Lys Lys Trp Thr Thr Phe Leu Lys 275 280 285 Ala Gln Leu Leu SerAla Pro Ser Arg Gly Ser Cys Pro Ser Thr Ser 290 295 300 Ser Ala Thr ArgSer Cys Ser Pro Pro Ile Leu Pro Gln Leu Pro Thr 305 310 315 320 Ser ThrGln Ser Ser Pro Pro Ser Gly Gln Val Gly Gly Thr Arg Ser 325 330 335 SerAla Val Cys Ala Phe Ser Leu Leu Asp Ile Glu Arg Val Phe Lys 340 345 350Gly Lys Phe Lys Glu Leu Asn Lys Glu Thr Ser Arg Trp Thr Thr Tyr 355 360365 Arg Gly Pro Glu Thr Asn Pro Arg Pro Gly Ser Cys Ser Val Gly Pro 370375 380 Ser Ser Asp Lys Ala Leu Thr Phe Met Lys Asp His Phe Leu Met Asp385 390 395 400 Glu Gln Val Val Gly Thr Pro Leu Leu Val Lys Ser Gly ValGlu Tyr 405 410 415 Thr Arg Leu Ala Val Glu Thr Ala Gln Gly Leu Asp GlyHis Ser His 420 425 430 Leu Val Met Tyr Leu Gly Thr Thr Thr Gly Ser LeuHis Lys Ala Val 435 440 445 Val Ser Gly Asp Ser Ser Ala His Leu Val GluGlu Ile Gln Leu Phe 450 455 460 Pro Asp Pro Glu Pro Val Arg Asn Leu GlnLeu Ala Pro Thr Gln Gly 465 470 475 480 Ala Val Phe Val Gly Phe Ser GlyGly Val Trp Arg Val Pro Arg Ala 485 490 495 Asn Cys Ser Val Tyr Glu SerCys Val Asp Cys Val Leu Ala Arg Asp 500 505 510 Pro His Cys Ala Trp AspPro Glu Ser Arg Thr Cys Cys Leu Leu Ser 515 520 525 Ala Pro Asn Leu AsnSer Trp Lys Gln Asp Met Glu Arg Gly Asn Pro 530 535 540 Glu Trp Ala CysAla Ser Gly Pro Met Ser Arg Ser Leu Arg Pro Gln 545 550 555 560 Ser ArgPro Gln Ile Ile Lys Glu Val Leu Ala Val Pro Asn Ser Ile 565 570 575 LeuGlu Leu Pro Cys Pro His Leu Ser Ala Leu Ala Ser Tyr Tyr Trp 580 585 590Ser His Gly Pro Ala Ala Val Pro Glu Ala Ser Ser Thr Val Tyr Asn 595 600605 Gly Ser Leu Leu Leu Ile Val Gln Asp Gly Val Gly Gly Leu Tyr Gln 610615 620 Cys Trp Ala Thr Glu Asn Gly Phe Ser Tyr Pro Val Ile Ser Tyr Trp625 630 635 640 Val Asp Ser Gln Asp Gln Thr Leu Ala Leu Asp Pro Glu LeuAla Gly 645 650 655 Ile Pro Arg Glu His Val Lys Val Pro Leu Thr Arg ValSer Gly Gly 660 665 670 Ala Ala Leu Ala Ala Gln Gln Ser Tyr Trp Pro HisPhe Val Thr Val 675 680 685 Thr Val Leu Phe Ala Leu Val Leu Ser Gly AlaLeu Ile Ile Leu Val 690 695 700 Ala Ser Pro Leu Arg Ala Leu Arg Ala ArgGly Lys Val Gln Gly Cys 705 710 715 720 Glu Thr Leu Arg Pro Gly Glu LysAla Pro Leu Ser Arg Glu Gln His 725 730 735 Leu Gln Ser Pro Lys Glu CysArg Thr Ser Ala Ser Asp Val Asp Ala 740 745 750 Asp Asn Asn Cys Leu GlyThr Glu Val Ala 755 760 36 760 PRT Mus musculus 36 Met Ala Leu Pro SerLeu Gly Gln Asp Ser Trp Ser Leu Leu Arg Val 1 5 10 15 Phe Phe Phe GlnLeu Phe Leu Leu Pro Ser Leu Pro Pro Ala Ser Gly 20 25 30 Thr Gly Gly GlnGly Pro Met Pro Arg Val Lys Tyr His Ala Gly Asp 35 40 45 Gly His Arg AlaLeu Ser Phe Phe Gln Gln Lys Gly Leu Arg Asp Phe 50 55 60 Asp Thr Leu LeuLeu Ser Asp Asp Gly Asn Thr Leu Tyr Val Gly Ala 65 70 75 80 Arg Glu ThrVal Leu Ala Leu Asn Ile Gln Asn Pro Gly Ile Pro Arg 85 90 95 Leu Lys AsnMet Ile Pro Trp Pro Ala Ser Glu Arg Lys Lys Thr Glu 100 105 110 Cys AlaPhe Lys Lys Lys Ser Asn Glu Thr Gln Cys Phe Asn Phe Ile 115 120 125 ArgVal Leu Val Ser Tyr Asn Ala Thr His Leu Tyr Ala Cys Gly Thr 130 135 140Phe Ala Phe Ser Pro Ala Cys Thr Phe Ile Glu Leu Gln Asp Ser Leu 145 150155 160 Leu Leu Pro Ile Leu Ile Asp Lys Val Met Asp Gly Lys Gly Gln Ser165 170 175 Pro Leu Thr Leu Phe Thr Ser Thr Gln Ala Val Leu Val Asp GlyMet 180 185 190 Leu Tyr Ser Gly Thr Met Asn Asn Phe Leu Gly Ser Glu ProIle Leu 195 200 205 Met Arg Thr Leu Gly Ser His Pro Val Leu Lys Thr AspIle Phe Leu 210 215 220 Arg Trp Leu His Ala Asp Ala Ser Phe Val Ala AlaIle Pro Ser Thr 225 230 235 240 Gln Val Val Tyr Phe Phe Phe Glu Glu ThrAla Ser Glu Phe Asp Phe 245 250 255 Phe Glu Glu Leu Tyr Ile Ser Arg ValAla Gln Val Cys Lys Asn Asp 260 265 270 Val Gly Gly Glu Lys Leu Leu GlnLys Lys Trp Thr Thr Phe Leu Lys 275 280 285 Ala Gln Leu Leu Cys Ala GlnPro Gly Gln Leu Pro Phe Asn Ile Ile 290 295 300 Arg His Ala Val Leu LeuPro Ala Asp Ser Pro Ser Val Ser Arg Ile 305 310 315 320 Tyr Ala Val PheThr Ser Gln Trp Gln Val Gly Gly Thr Arg Ser Ser 325 330 335 Ala Val CysAla Phe Ser Leu Thr Asp Ile Glu Arg Val Phe Lys Gly 340 345 350 Lys TyrLys Glu Leu Asn Lys Glu Thr Ser Arg Trp Thr Thr Tyr Arg 355 360 365 GlySer Glu Val Ser Pro Arg Pro Gly Ser Cys Ser Met Gly Pro Ser 370 375 380Ser Asp Lys Ala Leu Thr Phe Met Lys Asp His Phe Leu Met Asp Glu 385 390395 400 His Val Val Gly Thr Pro Leu Leu Val Lys Ser Gly Val Glu Tyr Thr405 410 415 Arg Leu Ala Val Glu Ser Ala Arg Gly Leu Asp Gly Ser Ser HisVal 420 425 430 Val Met Tyr Leu Gly Thr Ser Thr Gly Pro Leu His Lys AlaVal Val 435 440 445 Pro Gln Asp Ser Ser Ala Tyr Leu Val Glu Glu Ile GlnLeu Ser Pro 450 455 460 Asp Ser Glu Pro Val Arg Asn Leu Gln Leu Ala ProAla Gln Gly Ala 465 470 475 480 Val Phe Ala Gly Phe Ser Gly Gly Ile TrpArg Val Pro Arg Ala Asn 485 490 495 Cys Ser Val Tyr Glu Ser Cys Val AspCys Val Leu Ala Arg Asp Pro 500 505 510 His Cys Ala Trp Asp Pro Glu SerArg Leu Cys Ser Leu Leu Ser Gly 515 520 525 Ser Thr Lys Pro Trp Lys GlnAsp Met Glu Arg Gly Asn Pro Glu Trp 530 535 540 Val Cys Thr Arg Gly ProMet Ala Arg Ser Pro Arg Arg Gln Ser Pro 545 550 555 560 Pro Gln Leu IleLys Glu Val Leu Thr Val Pro Asn Ser Ile Leu Glu 565 570 575 Leu Arg CysPro His Leu Ser Ala Leu Ala Ser Tyr His Trp Ser His 580 585 590 Gly ArgAla Lys Ile Ser Glu Ala Ser Ala Thr Val Tyr Asn Gly Ser 595 600 605 LeuLeu Leu Leu Pro Gln Asp Gly Val Gly Gly Leu Tyr Gln Cys Val 610 615 620Ala Thr Glu Asn Gly Tyr Ser Tyr Pro Val Val Ser Tyr Trp Val Asp 625 630635 640 Ser Gln Asp Gln Pro Leu Ala Leu Asp Pro Glu Leu Ala Gly Val Pro645 650 655 Arg Glu Arg Val Gln Val Pro Leu Thr Arg Val Gly Gly Gly AlaSer 660 665 670 Met Ala Ala Gln Arg Ser Tyr Trp Pro His Phe Leu Ile ValThr Val 675 680 685 Leu Leu Ala Ile Val Leu Leu Gly Val Leu Thr Leu LeuLeu Ala Ser 690 695 700 Pro Leu Gly Ala Leu Arg Ala Arg Gly Lys Val GlnGly Cys Gly Met 705 710 715 720 Leu Pro Pro Arg Glu Lys Ala Pro Leu SerArg Asp Gln His Leu Gln 725 730 735 Pro Ser Lys Asp His Arg Thr Ser AlaSer Asp Val Asp Ala Asp Asn 740 745 750 Asn His Leu Gly Ala Glu Val Ala755 760 37 328 PRT Homo sapiens 37 Met Tyr Leu Gly Thr Thr Thr Gly SerLeu His Lys Ala Val Val Ser 1 5 10 15 Gly Asp Ser Ser Ala His Leu ValGlu Glu Ile Gln Leu Phe Pro Asp 20 25 30 Pro Glu Pro Val Arg Asn Leu GlnLeu Ala Pro Thr Gln Gly Ala Val 35 40 45 Phe Val Gly Phe Ser Gly Gly ValTrp Arg Val Pro Arg Ala Asn Cys 50 55 60 Ser Val Tyr Glu Ser Cys Val AspCys Val Leu Ala Arg Asp Pro His 65 70 75 80 Cys Ala Trp Asp Pro Glu SerArg Thr Cys Cys Leu Leu Ser Ala Pro 85 90 95 Asn Leu Asn Ser Trp Lys GlnAsp Met Glu Arg Gly Asn Pro Glu Trp 100 105 110 Ala Cys Ala Ser Gly ProMet Ser Arg Ser Leu Arg Pro Gln Ser Arg 115 120 125 Pro Gln Ile Ile LysGlu Val Leu Ala Val Pro Asn Ser Ile Leu Glu 130 135 140 Leu Pro Cys ProHis Leu Ser Ala Leu Ala Ser Tyr Tyr Trp Ser His 145 150 155 160 Gly ProAla Ala Val Pro Glu Ala Ser Ser Thr Val Tyr Asn Gly Ser 165 170 175 LeuLeu Leu Ile Val Gln Asp Gly Val Gly Gly Leu Tyr Gln Cys Trp 180 185 190Ala Thr Glu Asn Gly Phe Ser Tyr Pro Val Ile Ser Tyr Trp Val Asp 195 200205 Ser Gln Asp Gln Thr Leu Ala Leu Asp Pro Glu Leu Ala Gly Ile Pro 210215 220 Arg Glu His Val Lys Val Pro Leu Thr Arg Val Ser Gly Gly Ala Ala225 230 235 240 Leu Ala Ala Gln Gln Ser Tyr Trp Pro His Phe Val Thr ValThr Val 245 250 255 Leu Phe Ala Leu Val Leu Ser Gly Ala Leu Ile Ile LeuVal Ala Ser 260 265 270 Pro Leu Arg Ala Leu Arg Ala Arg Gly Lys Val GlnGly Cys Glu Thr 275 280 285 Leu Arg Pro Gly Glu Lys Ala Pro Leu Ser ArgGlu Gln His Leu Gln 290 295 300 Ser Pro Lys Glu Cys Arg Thr Ser Ala SerAsp Val Asp Ala Asp Asn 305 310 315 320 Asn Cys Leu Gly Thr Glu Val Ala325 38 893 PRT Homo sapiens 38 Val Cys Gln Gly Pro Leu Asp Pro Val SerHis Leu Pro Pro Pro Arg 1 5 10 15 Ser Gly Gly Gly Gly Pro Arg Gly AspSer Gly Ala Asp Arg Gly Ala 20 25 30 Glu Leu Pro Pro Val Ser Pro Ala GluPro Pro Glu Pro Glu Pro Arg 35 40 45 Asp Thr Val Ala Pro Ala Leu Arg MetLeu Arg Thr Ala Met Gly Leu 50 55 60 Arg Ser Trp Leu Ala Ala Pro Trp GlyAla Leu Pro Pro Arg Pro Pro 65 70 75 80 Leu Leu Leu Leu Leu Leu Leu LeuLeu Leu Leu Gln Pro Pro Pro Pro 85 90 95 Thr Trp Ala Leu Ser Pro Arg IleSer Leu Pro Leu Gly Ser Glu Glu 100 105 110 Arg Pro Phe Leu Arg Phe GluAla Glu His Ile Ser Asn Tyr Thr Ala 115 120 125 Leu Leu Leu Ser Arg AspGly Arg Thr Leu Tyr Val Gly Ala Arg Glu 130 135 140 Ala Leu Phe Ala LeuSer Ser Asn Leu Ser Phe Leu Pro Gly Gly Glu 145 150 155 160 Tyr Gln GluLeu Leu Trp Gly Ala Asp Ala Glu Lys Lys Gln Gln Cys 165 170 175 Ser PheLys Gly Lys Asp Pro Gln Arg Asp Cys Gln Asn Tyr Ile Lys 180 185 190 IleLeu Leu Pro Leu Ser Gly Ser His Leu Phe Thr Cys Gly Thr Ala 195 200 205Ala Phe Ser Pro Met Cys Thr Tyr Ile Asn Met Glu Asn Phe Thr Leu 210 215220 Ala Arg Asp Glu Lys Gly Asn Val Leu Leu Glu Asp Gly Lys Gly Arg 225230 235 240 Cys Pro Phe Asp Pro Asn Phe Lys Ser Thr Ala Leu Val Val AspGly 245 250 255 Glu Leu Tyr Thr Gly Thr Val Ser Ser Phe Gln Gly Asn AspPro Ala 260 265 270 Ile Ser Arg Ser Gln Ser Leu Arg Pro Thr Lys Thr GluSer Ser Leu 275 280 285 Asn Trp Leu Gln Asp Pro Ala Phe Val Ala Ser AlaTyr Ile Pro Glu 290 295 300 Ser Leu Gly Ser Leu Gln Gly Asp Asp Asp LysIle Tyr Phe Phe Phe 305 310 315 320 Ser Glu Thr Gly Gln Glu Phe Glu PhePhe Glu Asn Thr Ile Val Ser 325 330 335 Arg Ile Ala Arg Ile Cys Lys GlyAsp Glu Gly Gly Glu Arg Val Leu 340 345 350 Gln Gln Arg Trp Thr Ser PheLeu Lys Ala Gln Leu Leu Cys Ser Arg 355 360 365 Pro Asp Asp Gly Phe ProPhe Asn Val Leu Gln Asp Val Phe Thr Leu 370 375 380 Ser Pro Ser Pro GlnAsp Trp Arg Asp Thr Leu Phe Tyr Gly Val Phe 385 390 395 400 Thr Ser GlnTrp His Arg Gly Thr Thr Glu Gly Ser Ala Val Cys Val 405 410 415 Phe ThrMet Lys Asp Val Gln Arg Val Phe Ser Gly Leu Tyr Lys Glu 420 425 430 ValAsn Arg Glu Thr Gln Gln Trp Tyr Thr Val Thr His Pro Val Pro 435 440 445Thr Pro Arg Pro Gly Ala Cys Ile Thr Asn Ser Ala Arg Glu Arg Lys 450 455460 Ile Asn Ser Ser Leu Gln Leu Pro Asp Arg Val Leu Asn Phe Leu Lys 465470 475 480 Asp His Phe Leu Met Asp Gly Gln Val Arg Ser Arg Met Leu LeuLeu 485 490 495 Gln Pro Gln Ala Arg Tyr Gln Arg Val Ala Val His Arg ValPro Gly 500 505 510 Leu His His Thr Tyr Asp Val Leu Phe Leu Gly Thr GlyAsp Gly Arg 515 520 525 Leu His Lys Ala Val Ser Val Gly Pro Arg Val HisIle Ile Glu Glu 530 535 540 Leu Gln Ile Phe Ser Ser Gly Gln Pro Val GlnAsn Leu Leu Leu Asp 545 550 555 560 Thr His Arg Gly Leu Leu Tyr Ala AlaSer His Ser Gly Val Val Gln 565 570 575 Val Pro Met Ala Asn Cys Ser LeuTyr Arg Ser Cys Gly Asp Cys Leu 580 585 590 Leu Ala Arg Asp Pro Tyr CysAla Trp Ser Gly Ser Ser Cys Lys His 595 600 605 Val Ser Leu Tyr Gln ProGln Leu Ala Thr Arg Pro Trp Ile Gln Asp 610 615 620 Ile Glu Gly Ala SerAla Lys Asp Leu Cys Ser Ala Ser Ser Val Val 625 630 635 640 Ser Pro SerPhe Val Pro Thr Gly Glu Lys Pro Cys Glu Gln Val Gln 645 650 655 Phe GlnPro Asn Thr Val Asn Thr Leu Ala Cys Pro Leu Leu Ser Asn 660 665 670 LeuAla Thr Arg Leu Trp Leu Arg Asn Gly Ala Pro Val Asn Ala Ser 675 680 685Ala Ser Cys His Val Leu Pro Thr Gly Asp Leu Leu Leu Val Gly Thr 690 695700 Gln Gln Leu Gly Glu Phe Gln Cys Trp Ser Leu Glu Glu Gly Phe Gln 705710 715 720 Gln Leu Val Ala Ser Tyr Cys Pro Glu Val Val Glu Asp Gly ValAla 725 730 735 Asp Gln Thr Asp Glu Gly Gly Ser Val Pro Val Ile Ile SerThr Ser 740 745 750 Arg Val Ser Ala Pro Ala Gly Gly Lys Ala Ser Trp GlyAla Asp Arg 755 760 765 Ser Tyr Trp Lys Glu Phe Leu Val Met Cys Thr LeuPhe Val Leu Ala 770 775 780 Val Leu Leu Pro Val Leu Phe Leu Leu Tyr ArgHis Arg Asn Ser Met 785 790 795 800 Lys Val Phe Leu Lys Gln Gly Glu CysAla Ser Val His Pro Lys Thr 805 810 815 Cys Pro Val Val Leu Pro Pro GluThr Arg Pro Leu Asn Gly Leu Gly 820 825 830 Pro Pro Ser Thr Pro Leu AspHis Arg Gly Tyr Gln Ser Leu Ser Asp 835 840 845 Ser Pro Pro Gly Ser ArgVal Phe Thr Glu Ser Glu Lys Arg Pro Leu 850 855 860 Ser Ile Gln Asp SerPhe Val Glu Val Ser Pro Val Cys Pro Arg Pro 865 870 875 880 Arg Val ArgLeu Gly Ser Glu Ile Arg Asp Ser Val Val 885 890 39 782 PRT Mus musculus39 Glu Glu Arg Leu Ile Arg Lys Phe Glu Ala Glu Asn Ile Ser Asn Tyr 1 510 15 Thr Ala Leu Leu Leu Ser Gln Asp Gly Lys Thr Leu Tyr Val Gly Ala 2025 30 Arg Glu Ala Leu Phe Ala Leu Asn Ser Asn Leu Ser Phe Leu Pro Gly 3540 45 Gly Glu Tyr Gln Glu Leu Leu Trp Ser Ala Asp Ala Asp Arg Lys Gln 5055 60 Gln Cys Ser Phe Lys Gly Lys Asp Pro Lys Arg Asp Cys Gln Asn Tyr 6570 75 80 Ile Lys Ile Leu Leu Pro Leu Asn Ser Ser His Leu Leu Thr Cys Gly85 90 95 Thr Ala Ala Phe Ser Pro Leu Cys Ala Tyr Ile His Ile Ala Ser Phe100 105 110 Thr Leu Ala Gln Asp Glu Ala Gly Asn Val Ile Leu Glu Asp GlyLys 115 120 125 Gly His Cys Pro Phe Asp Pro Asn Phe Lys Ser Thr Ala LeuVal Val 130 135 140 Asp Gly Glu Leu Tyr Thr Gly Thr Val Ser Ser Phe GlnGly Asn Asp 145 150 155 160 Pro Ala Ile Ser Arg Ser Gln Ser Ser Arg ProThr Lys Thr Glu Ser 165 170 175 Ser Leu Asn Trp Leu Gln Asp Pro Ala PheVal Ala Ser Ala Thr Ser 180 185 190 Pro Glu Ser Leu Gly Ser Pro Ile GlyAsp Asp Asp Lys Ile Tyr Phe 195 200 205 Phe Phe Ser Glu Thr Gly Gln GluPhe Glu Phe Phe Glu Asn Thr Ile 210 215 220 Val Ser Arg Val Ala Arg ValCys Lys Gly Asp Glu Gly Gly Glu Arg 225 230 235 240 Val Leu Gln Gln ArgTrp Thr Ser Phe Leu Lys Ala Gln Leu Leu Cys 245 250 255 Ser Arg Pro AspAsp Gly Phe Pro Phe Asn Val Leu Gln Asp Val Phe 260 265 270 Thr Leu AsnPro Asn Pro Gln Asp Trp Arg Lys Thr Leu Ser Ile Gly 275 280 285 Val PheThr Ser Gln Trp His Arg Gly Thr Thr Glu Gly Ser Ala Ile 290 295 300 CysVal Phe Thr Met Asn Asp Val Gln Lys Ala Phe Asp Gly Leu Tyr 305 310 315320 Lys Lys Val Asn Arg Glu Thr Gln Gln Trp Tyr Thr Glu Thr His Gln 325330 335 Val Pro Thr Pro Arg Pro Gly Ala Cys Ile Thr Asn Ser Ala Arg Glu340 345 350 Arg Lys Ile Asn Ser Ser Leu Gln Leu Pro Asp Arg Val Leu AsnPhe 355 360 365 Leu Lys Asp His Phe Leu Met Asp Gly Gln Val Arg Ser ArgLeu Leu 370 375 380 Leu Leu Gln Pro Arg Ala Arg Tyr Gln Arg Val Ala ValHis Arg Val 385 390 395 400 Pro Gly Leu His Ser Thr Tyr Asp Val Leu PheLeu Gly Thr Gly Asp 405 410 415 Gly Arg Leu His Lys Ala Val Thr Leu SerSer Arg Val His Ile Ile 420 425 430 Glu Glu Leu Gln Ile Phe Pro Gln GlyGln Pro Val Gln Asn Leu Leu 435 440 445 Leu Asp Ser His Gly Gly Leu LeuTyr Ala Ser Ser His Ser Gly Val 450 455 460 Val Gln Val Pro Val Ala AsnCys Ser Leu Tyr Pro Thr Cys Gly Asp 465 470 475 480 Cys Leu Leu Ala ArgAsp Pro Tyr Cys Ala Trp Thr Gly Ser Ala Cys 485 490 495 Arg Leu Ala SerLeu Tyr Gln Pro Asp Leu Ala Ser Arg Pro Trp Thr 500 505 510 Gln Asp IleGlu Gly Ala Ser Val Lys Glu Leu Cys Lys Asn Ser Ser 515 520 525 Tyr LysAla Arg Phe Leu Val Pro Gly Lys Pro Cys Lys Gln Val Gln 530 535 540 IleGln Pro Asn Thr Val Asn Thr Leu Ala Cys Pro Leu Leu Ser Asn 545 550 555560 Leu Ala Thr Arg Leu Trp Val His Asn Gly Ala Pro Val Asn Ala Ser 565570 575 Ala Ser Cys Arg Val Leu Pro Thr Gly Asp Leu Leu Leu Val Gly Ser580 585 590 Gln Gln Gly Leu Gly Val Phe Gln Cys Trp Ser Ile Glu Glu GlyPhe 595 600 605 Gln Gln Leu Val Ala Ser Tyr Cys Pro Glu Val Met Glu GluGly Val 610 615 620 Met Asp Gln Lys Asn Gln Arg Asp Gly Thr Pro Val IleIle Asn Thr 625 630 635 640 Ser Arg Val Ser Ala Pro Ala Gly Gly Arg AspSer Trp Gly Ala Asp 645 650 655 Lys Ser Tyr Trp Asn Glu Phe Leu Val MetCys Thr Leu Phe Val Phe 660 665 670 Ala Met Val Leu Leu Phe Leu Phe PheLeu Tyr Arg His Arg Asp Gly 675 680 685 Met Lys Leu Phe Leu Lys Gln GlyGlu Cys Ala Ser Val His Pro Lys 690 695 700 Thr Arg Pro Ile Val Leu ProPro Glu Thr Arg Pro Leu Asn Gly Val 705 710 715 720 Gly Pro Pro Ser ThrPro Leu Asp His Arg Gly Tyr Gln Ala Leu Ser 725 730 735 Asp Ser Ser ProGly Pro Arg Val Phe Thr Glu Ser Glu Lys Arg Pro 740 745 750 Leu Ser IleGln Asp Ser Phe Val Glu Val Ser Pro Val Cys Pro Arg 755 760 765 Pro ArgVal Arg Leu Gly Ser Glu Ile Arg Asp Ser Val Val 770 775 780 40 257 PRTArtificial Sequence Description of Artificial Sequence Domain searchsequence 40 Gly Gly Leu Ala Gly Ile Ser Lys Pro Val Thr Leu Gln Thr SerTrp 1 5 10 15 Lys Asn Ala Tyr Lys Ser Gly Ala Trp Met Lys Asp Pro LeuTrp Asn 20 25 30 Thr Thr Lys Lys Ser Leu Tyr Trp Tyr Met Pro Leu Asn ThrArg Val 35 40 45 Leu Arg Ser Val Arg Glu Tyr Ser Ser Met Ser Asp Phe GlnMet Gly 50 55 60 Lys Asn Pro Thr Asp His Pro Leu Pro His Ala Gly Gln GlyThr Gly 65 70 75 80 Val Val Val Tyr Asn Gly Ser Leu Tyr Phe Asn Lys PheAsn Ser His 85 90 95 Asp Ile Cys Arg Phe Asp Leu Thr Thr Glu Thr Tyr GlnLys Glu Pro 100 105 110 Leu Leu Asn Gly Ala Gly Tyr Asn Asn Arg Phe ProTyr Ala Trp Gly 115 120 125 Gly Phe Ser Asp Ile Asp Leu Ala Val Asp GluAsn Gly Leu Trp Val 130 135 140 Ile Tyr Ala Thr Glu Gln Asn Ala Gly LysIle Val Ile Ser Lys Leu 145 150 155 160 Asn Pro Ala Thr Leu Thr Ile GluAsn Thr Trp Ile Thr Thr Tyr Asn 165 170 175 Lys Arg Ser Ala Ser Asn AlaPhe Met Ile Cys Gly Ile Leu Tyr Val 180 185 190 Thr Arg Ser Leu Gly SerLys Gly Glu Lys Val Phe Tyr Ala Tyr Asp 195 200 205 Thr Asn Thr Gly LysGlu Gly His Leu Asp Ile Pro Phe Glu Asn Met 210 215 220 Tyr Glu Tyr IleSer Met Leu Asp Tyr Asn Pro Asn Asp Arg Lys Leu 225 230 235 240 Tyr AlaTrp Asn Asn Gly His Leu Val His Tyr Asp Ile Ala Leu Lys 245 250 255 Pro41 1074 PRT Homo sapiens 41 Met Lys Gly Thr Cys Val Ile Ala Trp Leu PheSer Ser Leu Gly Leu 1 5 10 15 Trp Arg Leu Ala His Pro Glu Ala Gln GlyThr Thr Gln Cys Gln Arg 20 25 30 Thr Glu His Pro Val Ile Ser Tyr Lys GluIle Gly Pro Trp Leu Arg 35 40 45 Glu Phe Arg Ala Lys Asn Ala Val Asp PheSer Gln Leu Thr Phe Asp 50 55 60 Pro Gly Gln Lys Glu Leu Val Val Gly AlaArg Asn Tyr Leu Phe Arg 65 70 75 80 Leu Gln Leu Glu Asp Leu Ser Leu IleGln Ala Val Glu Trp Glu Cys 85 90 95 Asp Glu Ala Thr Lys Lys Ala Cys TyrSer Lys Gly Lys Ser Lys Glu 100 105 110 Glu Cys Gln Asn Tyr Ile Arg ValLeu Leu Val Gly Gly Asp Arg Leu 115 120 125 Phe Thr Cys Gly Thr Asn AlaPhe Thr Pro Val Cys Thr Asn Arg Ser 130 135 140 Leu Ser Asn Leu Thr GluIle His Asp Gln Ile Ser Gly Met Ala Arg 145 150 155 160 Cys Pro Tyr SerPro Gln His Asn Ser Thr Ala Leu Leu Thr Ala Gly 165 170 175 Gly Glu LeuTyr Ala Ala Thr Ala Met Asp Phe Pro Gly Arg Asp Pro 180 185 190 Ala IleTyr Arg Ser Leu Gly Ile Leu Pro Pro Leu Arg Thr Ala Gln 195 200 205 TyrAsn Ser Lys Trp Leu Asn Glu Pro Asn Phe Val Ser Ser Tyr Asp 210 215 220Ile Gly Asn Phe Thr Tyr Phe Phe Phe Arg Glu Asn Ala Val Glu His 225 230235 240 Asp Cys Gly Lys Thr Val Phe Ser Arg Ala Ala Arg Val Cys Lys Asn245 250 255 Asp Ile Gly Gly Arg Phe Leu Leu Glu Asp Thr Trp Thr Thr PheMet 260 265 270 Lys Ala Arg Leu Asn Cys Ser Arg Pro Gly Glu Val Pro PheTyr Tyr 275 280 285 Asn Glu Leu Gln Ser Thr Phe Phe Leu Pro Glu Leu AspLeu Ile Tyr 290 295 300 Gly Ile Phe Thr Thr Asn Val Asn Ser Ile Ala AlaSer Ala Val Cys 305 310 315 320 Val Phe Asn Leu Ser Ala Ile Ala Gln AlaPhe Ser Gly Pro Phe Lys 325 330 335 Tyr Gln Glu Asn Ser Arg Ser Ala TrpLeu Pro Tyr Pro Asn Pro Asn 340 345 350 Pro His Phe Gln Cys Gly Thr ValAsp Gln Gly Leu Tyr Val Asn Leu 355 360 365 Thr Glu Arg Asn Leu Gln AspAla Gln Lys Phe Ile Leu Met His Glu 370 375 380 Val Val Gln Pro Val ThrThr Val Pro Ser Phe Met Glu Asp Asn Ser 385 390 395 400 Arg Phe Ser HisVal Ala Val Asp Val Val Gln Gly Arg Glu Ala Leu 405 410 415 Val His IleIle Tyr Leu Ala Thr Asp Tyr Gly Thr Ile Lys Lys Val 420 425 430 Arg ValPro Leu Asn Gln Thr Ser Ser Ser Cys Leu Leu Glu Glu Ile 435 440 445 GluLeu Phe Pro Glu Arg Arg Arg Glu Pro Ile Arg Ser Leu Gln Ile 450 455 460Leu His Ser Gln Ser Val Leu Phe Val Gly Leu Arg Glu His Val Val 465 470475 480 Lys Ile Pro Leu Lys Arg Cys Gln Phe Tyr Arg Thr Arg Ser Thr Cys485 490 495 Ile Gly Ala Gln Asp Pro Tyr Cys Gly Trp Asp Val Val Met LysLys 500 505 510 Cys Thr Ser Leu Glu Glu Ser Leu Ser Met Thr Gln Trp GluGln Ser 515 520 525 Ile Ser Ala Cys Pro Thr Arg Asn Leu Thr Val Asp GlyHis Phe Gly 530 535 540 Val Trp Ser Pro Trp Thr Pro Cys Thr His Thr AspGly Ser Ala Val 545 550 555 560 Gly Ser Cys Leu Cys Arg Thr Arg Ser CysAsp Ser Pro Ala Pro Gln 565 570 575 Cys Gly Gly Trp Gln Cys Glu Gly ProGly Met Glu Ile Ala Asn Cys 580 585 590 Ser Arg Asn Gly Gly Trp Thr ProTrp Thr Ser Trp Ser Pro Cys Ser 595 600 605 Thr Thr Cys Gly Ile Gly PheGln Val Arg Gln Arg Ser Cys Ser Asn 610 615 620 Pro Thr Pro Arg His GlyGly Arg Val Cys Val Gly Gln Asn Arg Glu 625 630 635 640 Glu Arg Tyr CysAsn Glu His Leu Leu Cys Pro Pro His Met Phe Trp 645 650 655 Thr Gly TrpGly Pro Trp Glu Arg Cys Thr Ala Gln Cys Gly Gly Gly 660 665 670 Ile GlnAla Arg Arg Arg Ile Cys Glu Asn Gly Pro Asp Cys Ala Gly 675 680 685 CysAsn Val Glu Tyr Gln Ser Cys Asn Thr Asn Pro Cys Pro Glu Leu 690 695 700Lys Lys Thr Thr Pro Trp Thr Pro Trp Thr Pro Val Asn Ile Ser Asp 705 710715 720 Asn Gly Gly His Tyr Glu Gln Arg Phe Arg Tyr Thr Cys Lys Ala Arg725 730 735 Leu Ala Asp Pro Asn Leu Leu Glu Val Gly Arg Gln Arg Ile GluMet 740 745 750 Arg Tyr Cys Ser Ser Asp Gly Thr Ser Gly Cys Ser Thr AspGly Leu 755 760 765 Ser Gly Asp Phe Leu Arg Ala Gly Arg Tyr Ser Ala HisThr Val Asn 770 775 780 Gly Ala Trp Ser Ala Trp Thr Ser Trp Ser Gln CysSer Arg Asp Cys 785 790 795 800 Ser Arg Gly Ile Arg Asn Arg Lys Arg ValCys Asn Asn Pro Glu Pro 805 810 815 Lys Tyr Gly Gly Met Pro Cys Leu GlyPro Ser Leu Glu Tyr Gln Glu 820 825 830 Cys Asn Ile Leu Pro Cys Pro ValAsp Gly Val Trp Ser Cys Trp Ser 835 840 845 Pro Trp Thr Lys Cys Ser AlaThr Cys Gly Gly Gly His Tyr Met Arg 850 855 860 Thr Arg Ser Cys Ser AsnPro Ala Pro Ala Tyr Gly Gly Asp Ile Cys 865 870 875 880 Leu Gly Leu HisThr Glu Glu Ala Leu Cys Asn Thr Gln Pro Cys Pro 885 890 895 Glu Ser TrpSer Glu Trp Ser Asp Trp Ser Glu Cys Glu Ala Ser Gly 900 905 910 Val GlnVal Arg Ala Arg Gln Cys Ile Leu Leu Phe Pro Met Gly Ser 915 920 925 GlnCys Ser Gly Asn Thr Thr Glu Ser Arg Pro Cys Val Phe Asp Ser 930 935 940Asn Phe Ile Pro Glu Val Ser Val Ala Arg Ser Ser Ser Val Glu Glu 945 950955 960 Lys Arg Cys Gly Glu Phe Asn Met Phe His Met Ile Ala Val Gly Leu965 970 975 Ser Ser Ser Ile Leu Gly Cys Leu Leu Thr Leu Leu Val Tyr ThrTyr 980 985 990 Cys Gln Arg Tyr Gln Gln Gln Ser His Asp Ala Thr Val IleHis Pro 995 1000 1005 Val Ser Pro Ala Pro Leu Asn Thr Ser Ile Thr AsnHis Ile Asn Lys 1010 1015 1020 Leu Asp Lys Tyr Asp Ser Val Glu Ala IleLys Ala Phe Asn Lys Asn 1025 1030 1035 1040 Asn Leu Ile Leu Glu Glu ArgAsn Lys Tyr Phe Asn Pro His Leu Thr 1045 1050 1055 Gly Lys Thr Tyr SerAsn Ala Tyr Phe Thr Asp Leu Asn Asn Tyr Asp 1060 1065 1070 Glu Tyr 421093 PRT Mus musculus 42 Met Val Val Pro Gly Pro Leu Ala Leu Ser Leu LeuLeu Ser Ser Leu 1 5 10 15 Thr Leu Leu Val Ser His Leu Ser Ser Ser GlnAsp Ile Ala Ser Glu 20 25 30 Ser Ser Ser Glu Gln Gln Met Cys Thr Arg ArgGlu His Pro Ile Val 35 40 45 Ala Phe Glu Asp Leu Lys Pro Trp Val Phe AsnPhe Thr Tyr Pro Gly 50 55 60 Val Arg Asp Phe Ser Gln Leu Ala Leu Asp ProSer Arg Asn Gln Leu 65 70 75 80 Ile Val Gly Gly Arg Asn Tyr Leu Phe ArgLeu Ser Leu Ala Asn Val 85 90 95 Ser Leu Leu Gln Ala Thr Glu Trp Ala SerSer Glu Asp Thr Arg Arg 100 105 110 Ser Cys Gln Ser Lys Gly Lys Thr GluGlu Glu Cys Gln Asn Tyr Val 115 120 125 Arg Val Leu Ile Val Ser Gly ArgLys Val Phe Met Cys Gly Thr Asn 130 135 140 Ala Phe Ser Pro Val Cys SerSer Arg Gln Val Gly Asn Leu Ser Arg 145 150 155 160 Thr Ile Glu Lys IleAsn Gly Val Ala Arg Cys Pro Tyr Asp Pro Arg 165 170 175 His Asn Ser ThrAla Val Ile Ser Ser Gln Gly Glu Leu Tyr Ala Ala 180 185 190 Thr Val IleAsp Phe Ser Gly Arg Asp Pro Ala Ile Tyr Arg Ser Leu 195 200 205 Gly SerGly Pro Pro Leu Arg Thr Ala Gln Tyr Asn Ser Lys Trp Leu 210 215 220 AsnGlu Pro Asn Phe Val Ala Ala Phe Asp Ile Gly Leu Phe Ala Tyr 225 230 235240 Phe Phe Leu Arg Glu Asn Ala Val Glu His Asp Cys Gly Arg Thr Val 245250 255 Tyr Ser Arg Val Ala Arg Val Cys Lys Asn Asp Val Gly Gly Arg Phe260 265 270 Leu Leu Glu Asp Thr Trp Thr Thr Phe Met Lys Ala Arg Leu AsnCys 275 280 285 Ser Arg Pro Gly Glu Val Pro Phe Tyr Tyr Asn Glu Leu GlnSer Ala 290 295 300 Phe His Leu Pro Glu Gln Asp Leu Ile Tyr Gly Val PheThr Thr Asn 305 310 315 320 Val Asn Ser Ile Ala Ala Ser Ala Val Cys AlaPhe Asn Leu Ser Ala 325 330 335 Ile Ser Lys Ala Phe Asn Gly Pro Phe ArgTyr Gln Glu Asn Pro Arg 340 345 350 Ala Ala Trp Leu Pro Ile Ala Asn ProIle Pro Asn Phe Gln Cys Gly 355 360 365 Thr Leu Pro Glu Thr Gly Pro AsnGlu Asn Leu Thr Glu Arg Ser Leu 370 375 380 Gln Asp Ala Gln Arg Leu PheLeu Met Ser Glu Ala Val Gln Pro Val 385 390 395 400 Thr Pro Glu Pro CysVal Thr Gln Asp Ser Val Arg Phe Ser His Leu 405 410 415 Val Val Asp LeuVal Gln Ala Lys Asp Thr Leu Tyr His Val Leu Tyr 420 425 430 Ile Gly ThrGlu Ser Gly Thr Ile Leu Lys Ala Leu Ser Thr Ala Ser 435 440 445 Arg SerLeu Arg Gly Cys Tyr Leu Glu Glu Leu His Val Leu Pro Pro 450 455 460 GlyArg Leu Glu Pro Leu Arg Ser Leu Arg Ile Leu His Ser Ala Arg 465 470 475480 Ala Leu Phe Val Gly Leu Ser Asp Arg Val Leu Arg Ile Pro Leu Glu 485490 495 Arg Cys Ser Ala Tyr His Ser Gln Gly Ala Cys Leu Gly Ala Arg Asp500 505 510 Pro Tyr Cys Gly Trp Asp Gly Lys Arg Gln Leu Cys Ser Thr LeuGlu 515 520 525 Asp Ser Ser Asn Met Ser Leu Trp Ile Gln Asn Ile Thr ThrCys Pro 530 535 540 Val Arg Asn Val Thr Arg Asp Gly Gly Phe Gly Pro TrpSer Pro Trp 545 550 555 560 Lys Pro Cys Glu His Leu Asp Gly Asp Asn SerGly Ser Cys Leu Cys 565 570 575 Arg Ala Arg Ser Cys Asp Ser Pro Arg ProArg Cys Gly Gly Leu Glu 580 585 590 Cys Leu Gly Pro Ser Ile His Ile AlaAsn Cys Ser Arg Asn Gly Ala 595 600 605 Trp Thr Ala Trp Ser Ser Trp AlaGln Cys Ser Thr Ser Cys Gly Ile 610 615 620 Gly Phe Gln Val Arg Gln ArgSer Cys Ser Asn Pro Ala Pro Arg His 625 630 635 640 Gly Gly Arg Ile CysVal Gly Lys Ser Arg Glu Glu Arg Phe Cys Asn 645 650 655 Glu Asn Thr ProCys Pro Val Pro Ile Phe Trp Ala Ser Trp Gly Ser 660 665 670 Trp Ser LysCys Ser Asn Asn Cys Gly Gly Gly Val Gln Ser Arg Arg 675 680 685 Arg SerCys Glu Asn Gly Asn Ser Cys Pro Gly Cys Gly Val Glu Phe 690 695 700 LysThr Cys Asn Pro Glu Ala Cys Pro Glu Val Arg Arg Asn Thr Pro 705 710 715720 Trp Thr Pro Trp Leu Pro Val Asn Val Thr Gln Gly Gly Ala Arg Gln 725730 735 Glu Gln Arg Phe Arg Phe Thr Cys Arg Ala Pro Leu Pro Asp Pro His740 745 750 Gly Leu Gln Phe Gly Lys Arg Arg Thr Glu Thr Arg Thr Cys ProAla 755 760 765 Asp Gly Thr Gly Ala Cys Asp Thr Asp Ala Leu Val Glu AspLeu Leu 770 775 780 Arg Ser Gly Ser Thr Ser Pro His Thr Leu Asn Gly GlyTrp Ala Thr 785 790 795 800 Trp Gly Pro Trp Ser Ser Cys Ser Arg Asp CysGlu Leu Gly Phe Arg 805 810 815 Val Arg Lys Arg Thr Cys Thr Asn Pro GluPro Arg Asn Gly Gly Leu 820 825 830 Pro Cys Val Gly Asp Ala Ala Glu TyrGln Asp Cys Asn Pro Gln Ala 835 840 845 Cys Pro Val Arg Gly Ala Trp SerCys Trp Thr Ala Trp Ser Gln Cys 850 855 860 Ser Ala Ser Cys Gly Gly GlyHis Tyr Gln Arg Thr Arg Ser Cys Thr 865 870 875 880 Ser Pro Ala Pro SerPro Gly Glu Asp Ile Cys Leu Gly Leu His Thr 885 890 895 Glu Glu Ala LeuCys Ser Thr Gln Ala Cys Pro Glu Gly Trp Ser Leu 900 905 910 Trp Ser GluTrp Gly Val Cys Thr Glu Asp Gly Ala Gln Ser Arg Ser 915 920 925 Arg SerCys Glu Glu Leu Leu Pro Gly Pro Gly Ala Cys Val Gly Asn 930 935 940 SerSer Gln Ser Arg Pro Cys Pro Tyr Ser Glu Ile Pro Val Ile Leu 945 950 955960 Pro Ala Ser Ser Val Glu Glu Thr Thr Ser Cys Gly Gly Phe Asn Leu 965970 975 Ile His Leu Ile Val Thr Gly Val Ser Cys Phe Leu Val Ser Gly Leu980 985 990 Leu Thr Leu Ala Val Tyr Leu Ser Cys Gln His Cys Gln Arg GlnSer 995 1000 1005 Gln Glu Ser Thr Leu Val His Pro Ala Thr Pro Asn HisLeu His Tyr 1010 1015 1020 Lys Gly Gly Gly Thr Pro Lys Asn Glu Lys TyrThr Pro Met Glu Phe 1025 1030 1035 1040 Lys Thr Leu Asn Lys Asn Asn LeuIle Pro Asp Asp Arg Ala Asn Phe 1045 1050 1055 Tyr Pro Leu Gln Gln ThrAsn Val Tyr Thr Thr Thr Tyr Tyr Pro Ser 1060 1065 1070 Pro Leu Asn LysPro Ser Phe Arg Pro Glu Ala Ser Pro Gly Gln Arg 1075 1080 1085 Cys PhePro Asn Ser 1090 43 1077 PRT Mus musculus 43 Met Lys Gly Ala Cys Ile LeuAla Trp Leu Phe Ser Ser Leu Gly Val 1 5 10 15 Trp Arg Leu Ala Arg ProGlu Thr Gln Asp Pro Ala Lys Cys Gln Arg 20 25 30 Ala Glu His Pro Val ValSer Tyr Lys Glu Ile Gly Pro Trp Leu Arg 35 40 45 Glu Phe Arg Ala Glu AsnAla Val Asp Phe Ser Arg Leu Thr Phe Asp 50 55 60 Pro Gly Gln Lys Glu LeuVal Val Gly Ala Arg Asn Tyr Leu Phe Arg 65 70 75 80 Leu Glu Leu Glu AspLeu Ser Leu Ile Gln Ala Val Glu Trp Glu Cys 85 90 95 Asp Glu Ala Thr LysLys Ala Cys Tyr Ser Lys Gly Lys Ser Lys Glu 100 105 110 Glu Cys Gln AsnTyr Ile Arg Val Leu Leu Val Gly Gly Asp Arg Leu 115 120 125 Phe Thr CysGly Thr Asn Ala Phe Thr Pro Val Cys Thr Ile Arg Ser 130 135 140 Leu SerAsn Leu Thr Glu Ile His Asp Gln Ile Ser Gly Met Ala Arg 145 150 155 160Cys Pro Tyr Ser Pro Gln His Asn Ser Thr Ala Leu Leu Thr Ala Ser 165 170175 Gly Glu Leu Tyr Ala Ala Thr Ala Met Asp Phe Pro Gly Arg Asp Pro 180185 190 Ala Ile Tyr Arg Ser Leu Gly Thr Leu Pro Pro Leu Arg Thr Ala Gln195 200 205 Tyr Asn Ser Lys Trp Leu Asn Glu Pro Asn Phe Val Ser Ser TyrAsp 210 215 220 Ile Gly Asn Phe Thr Tyr Phe Phe Phe Arg Glu Asn Ala ValGlu His 225 230 235 240 Asp Cys Gly Lys Thr Val Phe Ser Arg Pro Ala ArgVal Cys Lys Asn 245 250 255 Asp Ile Gly Gly Arg Phe Leu Leu Glu Asp ThrTrp Thr Thr Phe Met 260 265 270 Lys Ala Arg Leu Asn Cys Ser Arg Pro GlyGlu Val Pro Phe Tyr Tyr 275 280 285 Asn Glu Leu Gln Gly Thr Phe Phe LeuPro Glu Leu Asp Leu Ile Tyr 290 295 300 Gly Ile Phe Thr Thr Asn Val AsnSer Ile Ala Ser Ser Ala Val Cys 305 310 315 320 Val Phe Asn Leu Ser AlaIle Ser Gln Ala Phe Asn Gly Pro Phe Lys 325 330 335 Tyr Gln Glu Asn SerArg Ser Ala Trp Leu Pro Tyr Pro Asn Pro Asn 340 345 350 Pro Asn Phe GlnCys Gly Thr Met Asp Gln Gly Leu Tyr Val Asn Leu 355 360 365 Thr Glu ArgAsn Leu Gln Asp Ala Gln Lys Phe Ile Leu Met His Glu 370 375 380 Val ValGln Pro Val Thr Thr Val Pro Ser Phe Met Glu Asp Asn Ser 385 390 395 400Arg Phe Ser His Leu Ala Val Asp Val Val Gln Gly Arg Glu Thr Leu 405 410415 Val His Ile Ile Tyr Leu Gly Thr Asp Tyr Gly Thr Ile Lys Lys Val 420425 430 Arg Ala Pro Leu Ser Gln Ser Ser Gly Ser Cys Leu Leu Glu Glu Ile435 440 445 Glu Leu Phe Pro Glu Arg Arg Ser Glu Pro Ile Arg Ser Leu GlnIle 450 455 460 Leu His Ser Gln Ser Val Leu Phe Val Gly Leu Gln Glu HisVal Ala 465 470 475 480 Lys Ile Pro Leu Lys Arg Cys His Phe His Gln ThrArg Ser Ala Cys 485 490 495 Ile Gly Ala Gln Asp Pro Tyr Cys Gly Trp AspAla Val Met Lys Lys 500 505 510 Cys Thr Ser Leu Glu Glu Ser Leu Ser MetThr Gln Trp Asp Gln Ser 515 520 525 Ile Pro Thr Cys Pro Thr Arg Asn LeuThr Val Asp Gly Ser Phe Gly 530 535 540 Pro Trp Ser Pro Trp Thr Pro CysThr His Thr Asp Gly Thr Ala Val 545 550 555 560 Gly Ser Cys Leu Cys ArgSer Arg Ser Cys Asp Arg Pro Ala Pro Gln 565 570 575 Cys Gly Gly Trp GlnCys Glu Gly Pro Arg Met Glu Ile Thr Asn Cys 580 585 590 Ser Arg Asn GlyGly Trp Thr Pro Trp Thr Ser Trp Ser Pro Cys Ser 595 600 605 Thr Thr CysGly Ile Gly Phe Gln Val Arg Gln Arg Ser Cys Ser Asn 610 615 620 Pro ThrPro Arg His Gly Gly Arg Val Cys Val Gly Gln Asn Arg Glu 625 630 635 640Glu Arg Tyr Cys Asn Glu His Leu Leu Cys Pro Pro His Val Phe Trp 645 650655 Thr Gly Trp Gly Pro Trp Glu Arg Cys Thr Ala Gln Cys Gly Gly Gly 660665 670 Ile Gln Ala Arg Arg Arg Thr Cys Glu Asn Gly Pro Asp Cys Ala Gly675 680 685 Ser Asn Val Glu Tyr His Pro Cys Asn Thr Asn Ala Cys Pro GluLeu 690 695 700 Lys Lys Thr Thr Pro Trp Thr Pro Trp Thr Pro Val Asn IleSer Asp 705 710 715 720 Asn Gly Gly His Tyr Glu Gln Arg Phe Arg Tyr ThrCys Lys Ala Arg 725 730 735 Leu Pro Asp Pro Asn Leu Leu Glu Val Gly ArgGln Arg Ile Glu Met 740 745 750 Arg Tyr Cys Ser Ser Asp Gly Thr Ser GlyCys Ser Thr Asp Gly Leu 755 760 765 Ser Gly Asp Phe Leu Arg Ala Gly ArgTyr Ser Ala His Thr Val Asn 770 775 780 Gly Ala Trp Ser Ala Trp Thr SerTrp Ser Gln Cys Ser Arg Asp Cys 785 790 795 800 Ser Arg Gly Ile Arg AsnArg Lys Arg Val Cys Asn Asn Pro Glu Pro 805 810 815 Lys Phe Gly Gly MetPro Cys Leu Gly Pro Ser Leu Glu Phe Gln Glu 820 825 830 Cys Asn Ile LeuPro Cys Pro Val Asp Gly Val Trp Ser Cys Trp Ser 835 840 845 Ser Trp SerLys Cys Ser Ala Thr Cys Gly Gly Gly His Tyr Met Arg 850 855 860 Thr ArgSer Cys Ser Asn Pro Ala Pro Ala Tyr Gly Gly Asp Ile Cys 865 870 875 880Leu Gly Leu His Thr Glu Glu Ala Leu Cys Asn Thr Gln Thr Cys Pro 885 890895 Glu Ser Trp Ser Glu Trp Ser Asp Trp Ser Val Cys Asp Ala Ser Gly 900905 910 Thr Gln Val Arg Ala Arg Gln Cys Ile Leu Leu Phe Pro Val Gly Ser915 920 925 Gln Cys Ser Gly Asn Thr Thr Glu Ser Arg Pro Cys Val Phe AspSer 930 935 940 Asn Phe Ile Pro Glu Val Ser Val Ala Arg Ser Ser Ser ValGlu Glu 945 950 955 960 Lys Arg Cys Gly Glu Phe Asn Met Phe His Met PheHis Met Met Ala 965 970 975 Val Gly Leu Ser Ser Ser Ile Leu Gly Cys LeuLeu Thr Leu Leu Val 980 985 990 Tyr Thr Tyr Cys Gln Arg Tyr Gln Gln GlnSer His Asp Ala Thr Val 995 1000 1005 Ile His Pro Val Ser Pro Ala AlaLeu Asn Ser Ser Ile Thr Asn His 1010 1015 1020 Ile Asn Lys Leu Asp LysTyr Asp Ser Val Glu Ala Ile Lys Ala Phe 1025 1030 1035 1040 Asn Lys AsnAsn Leu Ile Leu Glu Glu Arg Asn Lys Tyr Phe Asn Pro 1045 1050 1055 HisLeu Thr Gly Lys Thr Tyr Ser Asn Ala Tyr Phe Thr Asp Leu Asn 1060 10651070 Asn Tyr Asp Glu Tyr 1075 44 1074 PRT Homo sapiens 44 Met Lys GlyThr Cys Val Ile Ala Trp Leu Phe Ser Ser Leu Gly Leu 1 5 10 15 Trp ArgLeu Ala His Pro Glu Ala Gln Gly Thr Thr Gln Cys Gln Arg 20 25 30 Thr GluHis Pro Val Ile Ser Tyr Lys Glu Ile Gly Pro Trp Leu Arg 35 40 45 Glu PheArg Ala Lys Asn Ala Ala Asp Phe Ser Gln Leu Thr Phe Asp 50 55 60 Pro GlyGln Lys Glu Leu Val Val Gly Ala Arg Asn Tyr Leu Phe Arg 65 70 75 80 LeuGln Leu Glu Asp Leu Ser Leu Ile Gln Ala Val Glu Trp Glu Cys 85 90 95 AspGlu Ala Thr Lys Lys Ala Cys Tyr Ser Lys Gly Lys Ser Lys Glu 100 105 110Glu Cys Gln Asn Tyr Ile Arg Val Leu Leu Val Gly Gly Asp Arg Leu 115 120125 Phe Thr Cys Gly Thr Asn Ala Phe Thr Pro Val Cys Thr Asn Arg Ser 130135 140 Leu Ser Asn Leu Ala Glu Ile His Asp Gln Ile Ser Gly Met Ala Arg145 150 155 160 Cys Pro Tyr Ser Pro Gln His Asn Ser Thr Ala Leu Leu ThrAla Gly 165 170 175 Gly Glu Leu Tyr Ala Ala Thr Ala Met Asp Phe Pro GlyArg Asp Pro 180 185 190 Ala Ile Tyr Arg Ser Leu Gly Ile Leu Pro Pro LeuArg Thr Ala Gln 195 200 205 Tyr Asn Ser Lys Trp Leu Asn Glu Pro Asn PheVal Ser Ser Tyr Asp 210 215 220 Ile Gly Asn Phe Thr Tyr Phe Phe Phe ArgGlu Asn Ala Val Glu His 225 230 235 240 Asp Cys Gly Lys Thr Val Phe SerArg Ala Ala Arg Val Cys Lys Asn 245 250 255 Asp Ile Gly Gly Arg Phe LeuLeu Glu Asp Thr Trp Thr Thr Phe Met 260 265 270 Lys Ala Arg Leu Asn CysSer Arg Pro Gly Glu Val Pro Phe Tyr Tyr 275 280 285 Asn Glu Leu Gln SerThr Phe Phe Leu Pro Glu Leu Asp Leu Ile Tyr 290 295 300 Gly Ile Phe ThrThr Asn Val Asn Ser Ile Ala Ala Ser Ala Val Cys 305 310 315 320 Val PheAsn Leu Ser Ala Ile Ala Gln Ala Phe Ser Gly Pro Phe Lys 325 330 335 TyrGln Glu Asn Ser Arg Ser Ala Trp Leu Pro Tyr Pro Asn Pro Asn 340 345 350Pro His Phe Gln Cys Gly Thr Val Asp Gln Gly Leu Tyr Val Asn Leu 355 360365 Thr Glu Arg Asn Leu Gln Asp Ala Gln Lys Phe Ile Leu Val His Glu 370375 380 Val Val Gln Pro Val Thr Thr Val Pro Ser Phe Met Glu Asp Asn Ser385 390 395 400 Arg Phe Ser His Val Ala Val Asp Val Val Gln Gly Arg GluAla Leu 405 410 415 Val His Ile Ile Tyr Leu Ala Thr Asp Tyr Gly Thr IleLys Lys Val 420 425 430 Arg Val Pro Leu Asn Gln Thr Ser Ser Ser Cys LeuLeu Glu Glu Ile 435 440 445 Glu Leu Phe Pro Glu Arg Arg Arg Glu Pro IleArg Ser Leu Gln Ile 450 455 460 Leu His Ser Gln Ser Val Leu Phe Val GlyLeu Arg Glu His Val Val 465 470 475 480 Lys Ile Pro Leu Lys Arg Cys GlnPhe Tyr Arg Thr Arg Ser Thr Cys 485 490 495 Ile Gly Ala Gln Asp Pro TyrCys Gly Trp Asp Val Val Met Lys Lys 500 505 510 Cys Thr Ser Leu Glu GluSer Leu Ser Met Thr Gln Trp Glu Gln Ser 515 520 525 Ile Ser Ala Cys ProThr Arg Asn Leu Thr Val Asp Gly His Phe Gly 530 535 540 Val Trp Ser ProTrp Thr Pro Cys Thr His Thr Asp Gly Ser Ala Val 545 550 555 560 Gly SerCys Leu Cys Arg Thr Arg Ser Cys Asp Ser Pro Ala Pro Gln 565 570 575 CysGly Gly Trp Gln Cys Glu Gly Pro Gly Met Glu Ile Ala Asn Cys 580 585 590Ser Arg Asn Gly Gly Trp Thr Pro Trp Thr Ser Trp Ser Pro Cys Ser 595 600605 Thr Thr Cys Gly Ile Gly Phe Gln Val Arg Gln Arg Ser Cys Ser Asn 610615 620 Pro Thr Pro Arg His Gly Gly Arg Val Cys Val Gly Gln Asn Arg Glu625 630 635 640 Glu Arg Tyr Cys Asn Glu His Leu Leu Cys Pro Pro His MetPhe Trp 645 650 655 Thr Gly Trp Gly Pro Trp Glu Arg Cys Thr Ala Gln CysGly Gly Gly 660 665 670 Ile Gln Ala Arg Arg Arg Ile Cys Glu Asn Gly ProAsp Cys Ala Gly 675 680 685 Cys Asn Val Glu Tyr Gln Ser Cys Asn Thr AsnPro Cys Pro Glu Leu 690 695 700 Lys Lys Thr Thr Pro Trp Thr Pro Trp ThrPro Val Asn Ile Ser Asp 705 710 715 720 Asn Gly Asp His Tyr Glu Gln ArgPhe Arg Tyr Thr Cys Lys Ala Arg 725 730 735 Leu Ala Asp Pro Asn Leu LeuGlu Val Gly Arg Gln Arg Ile Glu Met 740 745 750 Arg Tyr Cys Ser Ser AspGly Thr Ser Gly Cys Ser Thr Asp Gly Leu 755 760 765 Ser Gly Asp Phe LeuArg Ala Gly Arg Tyr Ser Ala His Thr Val Asn 770 775 780 Gly Ala Trp SerAla Trp Thr Ser Trp Ser Gln Cys Ser Arg Asp Cys 785 790 795 800 Ser ArgGly Ile Arg Asn Arg Lys Arg Val Cys Asn Asn Pro Glu Pro 805 810 815 LysTyr Gly Gly Met Pro Cys Leu Gly Pro Ser Leu Glu Tyr Gln Glu 820 825 830Cys Asn Thr Leu Pro Cys Pro Val Asp Gly Val Trp Ser Cys Trp Ser 835 840845 Pro Trp Thr Lys Cys Ser Ala Thr Cys Gly Gly Gly His Tyr Met Arg 850855 860 Thr Arg Ser Cys Ser Asn Pro Ala Pro Ala Tyr Gly Gly Asp Ile Cys865 870 875 880 Leu Gly Leu His Thr Glu Glu Ala Leu Cys Asn Thr Gln ProCys Pro 885 890 895 Glu Ser Trp Ser Glu Trp Ser Asp Trp Ser Glu Cys GluAla Ser Gly 900 905 910 Val Gln Val Arg Ala Arg Gln Cys Ile Leu Leu PhePro Met Gly Ser 915 920 925 Gln Cys Ser Gly Asn Thr Thr Glu Ser Arg ProCys Val Phe Asp Ser 930 935 940 Asn Phe Ile Pro Glu Val Ser Val Ala ArgSer Ser Ser Val Glu Glu 945 950 955 960 Lys Arg Cys Gly Glu Phe Asn MetPhe His Met Ile Ala Val Gly Leu 965 970 975 Ser Ser Ser Ile Leu Gly CysLeu Leu Thr Leu Leu Val Tyr Thr Tyr 980 985 990 Cys Gln Arg Tyr Gln GlnGln Ser His Asp Ala Thr Val Ile His Pro 995 1000 1005 Val Ser Pro AlaPro Leu Asn Thr Ser Ile Thr Asn His Ile Asn Lys 1010 1015 1020 Leu AspLys Tyr Asp Ser Val Glu Ala Ile Lys Ala Phe Asn Lys Asn 1025 1030 10351040 Asn Leu Ile Leu Glu Glu Arg Asn Lys Tyr Phe Asn Pro His Leu Thr1045 1050 1055 Gly Lys Thr Tyr Ser Asn Ala Tyr Phe Thr Asp Leu Asn AsnTyr Asp 1060 1065 1070 Glu Tyr 45 1202 PRT Homo sapiens 45 Ala Ala AlaPro Phe Pro Asp Arg Pro Pro Ala His Leu Val Ser Ser 1 5 10 15 Arg ArgSer Ala Pro Pro Gly Ser Arg Glu Pro Arg Gly Thr Gly His 20 25 30 Leu HisPro Pro Leu Gly Val Ser Gly Ser Ser Trp Cys Leu Ala Cys 35 40 45 Val SerTrp Met Pro Cys Gly Phe Ser Pro Ser Pro Val Ala His His 50 55 60 Leu ValPro Gly Pro Pro Asp Thr Pro Ala Gln Gln Leu Arg Cys Gly 65 70 75 80 TrpThr Val Gly Gly Trp Leu Leu Ser Leu Val Arg Gly Leu Leu Pro 85 90 95 CysLeu Pro Pro Gly Ala Arg Thr Ala Glu Gly Pro Ile Met Val Leu 100 105 110Ala Gly Pro Leu Ala Val Ser Leu Leu Leu Pro Ser Leu Thr Leu Leu 115 120125 Val Ser His Leu Ser Ser Ser Gln Asp Val Ser Ser Glu Pro Ser Ser 130135 140 Glu Gln Gln Leu Cys Ala Leu Ser Lys His Pro Thr Val Ala Phe Glu145 150 155 160 Asp Leu Gln Pro Trp Val Ser Asn Phe Thr Tyr Pro Gly AlaArg Asp 165 170 175 Phe Ser Gln Leu Ala Leu Asp Pro Ser Gly Asn Gln LeuIle Val Gly 180 185 190 Ala Arg Asn Tyr Leu Phe Arg Leu Ser Leu Ala AsnVal Ser Leu Leu 195 200 205 Gln Ala Thr Glu Trp Ala Ser Ser Glu Asp ThrArg Arg Ser Cys Gln 210 215 220 Ser Lys Gly Lys Thr Glu Glu Glu Cys GlnAsn Tyr Val Arg Val Leu 225 230 235 240 Ile Val Ala Gly Arg Lys Val PheMet Cys Gly Thr Asn Ala Phe Ser 245 250 255 Pro Met Cys Thr Ser Arg GlnVal Gly Asn Leu Ser Arg Thr Thr Glu 260 265 270 Lys Ile Asn Gly Val AlaArg Cys Pro Tyr Asp Pro Arg His Asn Ser 275 280 285 Thr Ala Val Ile SerSer Gln Gly Glu Leu Tyr Ala Ala Thr Val Ile 290 295 300 Asp Phe Ser GlyArg Asp Pro Ala Ile Tyr Arg Ser Leu Gly Ser Gly 305 310 315 320 Pro ProLeu Arg Thr Ala Gln Tyr Asn Ser Lys Trp Leu Asn Glu Pro 325 330 335 AsnPhe Val Ala Ala Tyr Asp Ile Gly Leu Phe Ala Tyr Phe Phe Leu 340 345 350Arg Glu Asn Ala Val Glu His Asp Cys Gly Arg Thr Val Tyr Ser Arg 355 360365 Val Ala Arg Val Cys Lys Asn Asp Val Gly Gly Arg Phe Leu Leu Glu 370375 380 Asp Thr Trp Thr Thr Phe Met Lys Ala Arg Leu Asn Cys Ser Arg Pro385 390 395 400 Gly Glu Val Pro Phe Tyr Tyr Asn Glu Leu Gln Ser Ala PheHis Leu 405 410 415 Pro Glu Gln Asp Leu Ile Tyr Gly Val Phe Thr Thr AsnVal Asn Ser 420 425 430 Ile Ala Ala Ser Ala Val Cys Ala Phe Asn Leu SerAla Ile Ser Gln 435 440 445 Ala Phe Asn Gly Pro Phe Arg Tyr Gln Glu AsnPro Arg Ala Ala Trp 450 455 460 Leu Pro Ile Ala Asn Pro Ile Pro Asn PheGln Cys Gly Thr Leu Pro 465 470 475 480 Glu Thr Gly Pro Asn Glu Asn LeuThr Glu Arg Ser Leu Gln Asp Ala 485 490 495 Gln Arg Leu Phe Leu Met SerGlu Ala Val Gln Pro Val Thr Pro Glu 500 505 510 Pro Cys Val Thr Gln AspSer Val Arg Phe Ser His Leu Val Val Asp 515 520 525 Leu Val Gln Ala LysAsp Thr Leu Tyr His Val Leu Tyr Ile Gly Thr 530 535 540 Glu Ser Gly ThrIle Leu Lys Ala Leu Ser Thr Ala Ser Arg Ser Leu 545 550 555 560 His GlyCys Tyr Leu Glu Glu Leu His Val Leu Pro Pro Gly Arg Arg 565 570 575 GluPro Leu Arg Ser Leu Arg Ile Leu His Ser Ala Arg Ala Leu Phe 580 585 590Val Gly Leu Arg Asp Gly Val Leu Arg Val Pro Leu Glu Arg Cys Ala 595 600605 Ala Tyr Arg Ser Gln Gly Ala Cys Leu Gly Ala Arg Asp Pro Tyr Cys 610615 620 Gly Trp Asp Gly Lys Gln Gln Arg Cys Ser Thr Leu Glu Asp Ser Ser625 630 635 640 Asn Met Ser Leu Trp Thr Gln Asn Ile Thr Ala Cys Pro ValArg Asn 645 650 655 Val Thr Arg Asp Gly Gly Phe Gly Pro Trp Ser Pro TrpGln Pro Cys 660 665 670 Glu His Leu Asp Gly Asp Asn Ser Gly Ser Cys LeuCys Arg Ala Arg 675 680 685 Ser Cys Asp Ser Pro Arg Pro Arg Cys Gly GlyLeu Asp Cys Leu Gly 690 695 700 Pro Ala Ile His Ile Ala Asn Cys Ser ArgAsn Gly Ala Trp Thr Pro 705 710 715 720 Trp Ser Ser Trp Ala Leu Cys SerThr Ser Cys Gly Ile Gly Phe Gln 725 730 735 Val Arg Gln Arg Ser Cys SerAsn Pro Ala Pro Arg His Gly Gly Arg 740 745 750 Ile Cys Val Gly Lys SerArg Glu Glu Arg Phe Cys Asn Glu Asn Thr 755 760 765 Pro Cys Pro Val ProIle Phe Trp Ala Ser Trp Gly Ser Trp Ser Lys 770 775 780 Cys Ser Ser AsnCys Gly Gly Gly Met Gln Ser Arg Arg Arg Ala Cys 785 790 795 800 Glu AsnGly Asn Ser Cys Leu Gly Cys Gly Val Glu Phe Lys Thr Cys 805 810 815 AsnPro Glu Gly Cys Pro Glu Val Arg Arg Asn Thr Pro Trp Thr Pro 820 825 830Trp Leu Pro Val Asn Val Thr Gln Gly Gly Ala Arg Gln Glu Gln Arg 835 840845 Phe Arg Phe Thr Cys Arg Ala Pro Leu Ala Asp Pro His Gly Leu Gln 850855 860 Phe Gly Arg Arg Arg Thr Glu Thr Arg Thr Cys Pro Ala Asp Gly Ser865 870 875 880 Gly Ser Cys Asp Thr Asp Ala Leu Val Glu Asp Leu Leu ArgSer Gly 885 890 895 Ser Thr Ser Pro His Thr Val Ser Gly Gly Trp Ala AlaTrp Gly Pro 900 905 910 Trp Ser Ser Cys Ser Arg Asp Cys Glu Leu Gly PheArg Val Arg Lys 915 920 925 Arg Thr Cys Thr Asn Pro Glu Pro Arg Asn GlyGly Leu Pro Cys Val 930 935 940 Gly Asp Ala Ala Glu Tyr Gln Asp Cys AsnPro Gln Ala Cys Pro Val 945 950 955 960 Arg Gly Ala Trp Ser Cys Trp ThrSer Trp Ser Pro Cys Ser Ala Ser 965 970 975 Cys Gly Gly Gly His Tyr GlnArg Thr Arg Ser Cys Thr Ser Pro Ala 980 985 990 Pro Ser Pro Gly Glu AspIle Cys Leu Gly Leu His Thr Glu Glu Ala 995 1000 1005 Leu Cys Ala ThrGln Ala Cys Pro Glu Gly Trp Ser Pro Trp Ser Glu 1010 1015 1020 Trp SerLys Cys Thr Asp Asp Gly Ala Gln Ser Arg Ser Arg His Cys 1025 1030 10351040 Glu Glu Leu Leu Pro Gly Ser Ser Ala Cys Ala Gly Asn Ser Ser Gln1045 1050 1055 Ser Arg Pro Cys Pro Tyr Ser Glu Ile Pro Val Ile Leu ProAla Ser 1060 1065 1070 Ser Met Glu Glu Ala Thr Gly Cys Ala Gly Phe AsnLeu Ile His Leu 1075 1080 1085 Val Ala Thr Gly Ile Ser Cys Phe Leu GlySer Gly Leu Leu Thr Leu 1090 1095 1100 Ala Val Tyr Leu Ser Cys Gln HisCys Gln Arg Gln Ser Gln Glu Ser 1105 1110 1115 1120 Thr Leu Val His ProAla Thr Pro Asn His Leu His Tyr Lys Gly Gly 1125 1130 1135 Gly Thr ProLys Asn Glu Lys Tyr Thr Pro Met Glu Phe Lys Thr Leu 1140 1145 1150 AsnLys Asn Asn Leu Ile Pro Asp Asp Arg Ala Asn Phe Tyr Pro Leu 1155 11601165 Gln Gln Thr Asn Val Tyr Thr Thr Thr Tyr Tyr Pro Ser Pro Leu Asn1170 1175 1180 Lys His Ser Phe Arg Pro Glu Ala Ser Pro Gly Gln Arg CysPhe Pro 1185 1190 1195 1200 Asn Ser 46 963 PRT Homo sapiens 46 Leu CysSer His Leu Trp Gln Pro Gly Leu Gly Ser Cys Trp Ser Glu 1 5 10 15 GlyPhe Pro Glu Ala Gly Ser Thr His Ser Arg Leu Cys Leu Leu Leu 20 25 30 CysTrp Thr Leu Ile Glu Ala Val Gly Ser Arg Ala Lys Lys Glu Ala 35 40 45 AlaAla Glu Glu Ala Lys Val Gly Trp Gly Cys Pro Ala Leu Arg Pro 50 55 60 GluVal Pro Leu Thr Leu Arg Ala Arg Ala Ile Ser Leu Met Ala Ser 65 70 75 80Ser Gly Arg Lys Leu Trp Leu Arg Tyr Pro Ser Phe Leu Pro Ala Ala 85 90 95Trp Ile Cys Leu Leu Pro Gly Trp Glu Arg Leu Gly Arg Pro Arg Trp 100 105110 Gly Cys Gln Gly Gln Arg Leu Phe Gln Lys Cys Pro Leu Leu Pro Ile 115120 125 Arg Gly Phe Gly Trp His Leu Leu Val Ala Trp Gly Ala Gly Ser Arg130 135 140 Gly Ala Arg Leu Arg Ala Val Glu Pro Gln Gly Ser Cys Pro SerAla 145 150 155 160 Ala Met Leu Thr Pro Ala Glu Leu Ala Thr Val Val ArgArg Phe Ser 165 170 175 Gln Thr Gly Ile Gln Asp Phe Leu Thr Leu Thr LeuThr Glu Pro Thr 180 185 190 Gly Leu Leu Tyr Val Gly Ala Arg Glu Ala LeuPhe Ala Phe Ser Met 195 200 205 Glu Ala Leu Glu Leu Gln Gly Ala Ile SerTrp Glu Ala Pro Val Glu 210 215 220 Lys Lys Thr Glu Cys Ile Gln Lys GlyLys Asn Asn Gln Thr Glu Cys 225 230 235 240 Phe Asn Phe Ile Arg Phe LeuGln Pro Tyr Asn Ala Ser His Leu Tyr 245 250 255 Val Cys Gly Thr Tyr AlaPhe Gln Pro Lys Cys Thr Tyr Val Asn Met 260 265 270 Leu Thr Phe Thr LeuGlu His Gly Glu Phe Glu Asp Gly Lys Gly Lys 275 280 285 Cys Pro Tyr AspPro Ala Lys Gly His Ala Gly Leu Leu Val Asp Gly 290 295 300 Glu Leu TyrSer Ala Thr Leu Asn Asn Phe Leu Gly Thr Glu Pro Ile 305 310 315 320 IleLeu Arg Asn Met Gly Pro His His Ser Met Lys Thr Glu Tyr Leu 325 330 335Ala Phe Trp Leu Asn Glu Pro His Phe Val Gly Ser Ala Tyr Val Pro 340 345350 Glu Ser Val Gly Ser Phe Thr Gly Asp Asp Asp Lys Val Tyr Phe Phe 355360 365 Phe Arg Glu Arg Ala Val Glu Ser Asp Cys Tyr Ala Glu Gln Val Val370 375 380 Ala Arg Val Ala Arg Val Cys Lys Gly Asp Met Gly Gly Ala ArgThr 385 390 395 400 Leu Gln Arg Lys Trp Thr Thr Phe Leu Lys Ala Arg LeuAla Cys Ser 405 410 415 Ala Pro Asn Trp Gln Leu Tyr Phe Asn Gln Leu GlnAla Met His Thr 420 425 430 Leu Gln Asp Thr Ser Trp His Asn Thr Thr PhePhe Gly Val Phe Gln 435 440 445 Ala Gln Trp Gly Asp Met Tyr Leu Ser AlaIle Cys Glu Tyr Gln Leu 450 455 460 Glu Glu Ile Gln Arg Val Phe Glu GlyPro Tyr Lys Glu Tyr His Glu 465 470 475 480 Glu Ala Gln Lys Trp Asp ArgTyr Thr Asp Pro Val Pro Ser Pro Arg 485 490 495 Pro Gly Ser Cys Ile AsnAsn Trp His Arg Arg His Gly Tyr Thr Ser 500 505 510 Ser Leu Glu Leu ProAsp Asn Ile Leu Asn Phe Val Lys Lys His Pro 515 520 525 Leu Met Glu GluGln Val Gly Pro Arg Trp Ser Arg Pro Leu Leu Val 530 535 540 Lys Lys GlyThr Asn Phe Thr His Leu Val Ala Asp Arg Val Thr Gly 545 550 555 560 LeuAsp Gly Ala Thr Tyr Thr Val Leu Phe Ile Gly Thr Gly Asp Gly 565 570 575Trp Leu Leu Lys Ala Val Ser Leu Gly Pro Trp Val His Leu Ile Glu 580 585590 Glu Leu Gln Leu Phe Asp Gln Glu Pro Met Arg Ser Leu Val Leu Ser 595600 605 Gln Ser Lys Lys Leu Leu Phe Ala Gly Ser Arg Ser Gln Leu Val Gln610 615 620 Leu Pro Val Ala Asp Cys Met Lys Tyr Arg Ser Cys Ala Asp CysVal 625 630 635 640 Leu Ala Arg Asp Pro Tyr Cys Ala Trp Ser Val Asn ThrSer Arg Cys 645 650 655 Val Ala Val Gly Gly His Ser Gly Ser Leu Leu IleGln His Val Met 660 665 670 Thr Ser Asp Thr Ser Gly Ile Cys Asn Leu ArgGly Ser Lys Lys Val 675 680 685 Arg Pro Thr Pro Lys Asn Ile Thr Val ValAla Gly Thr Asp Leu Val 690 695 700 Leu Pro Cys His Leu Ser Ser Asn LeuAla His Ala Arg Trp Thr Phe 705 710 715 720 Gly Gly Arg Asp Leu Pro AlaGlu Gln Pro Gly Ser Phe Leu Tyr Asp 725 730 735 Ala Arg Leu Gln Ala LeuVal Val Met Ala Ala Gln Pro Arg His Ala 740 745 750 Gly Ala Tyr His CysPhe Ser Glu Glu Gln Gly Ala Arg Leu Ala Ala 755 760 765 Glu Gly Tyr LeuVal Ala Val Val Ala Gly Pro Ser Val Thr Leu Glu 770 775 780 Ala Arg AlaPro Leu Glu Asn Leu Gly Leu Val Trp Leu Ala Val Val 785 790 795 800 AlaLeu Gly Ala Val Cys Leu Val Leu Leu Leu Leu Val Leu Ser Leu 805 810 815Arg Arg Arg Leu Arg Glu Glu Leu Glu Lys Gly Ala Lys Ala Thr Glu 820 825830 Arg Thr Leu Val Tyr Pro Leu Glu Leu Pro Lys Glu Pro Thr Ser Pro 835840 845 Pro Phe Arg Pro Cys Pro Glu Pro Asp Glu Lys Leu Trp Asp Pro Val850 855 860 Gly Tyr Tyr Tyr Ser Asp Gly Ser Leu Lys Ile Val Pro Gly HisAla 865 870 875 880 Arg Cys Gln Pro Gly Gly Gly Pro Pro Ser Pro Pro ProGly Ile Pro 885 890 895 Gly Gln Pro Leu Pro Ser Pro Thr Arg Leu His LeuGly Gly Gly Arg 900 905 910 Asn Ser Asn Ala Asn Gly Tyr Val Arg Leu GlnLeu Gly Gly Glu Asp 915 920 925 Arg Gly Gly Leu Gly His Pro Leu Pro GluLeu Ala Asp Glu Leu Arg 930 935 940 Arg Lys Leu Gln Gln Arg Gln Pro LeuPro Asp Ser Asn Pro Glu Glu 945 950 955 960 Ser Ser Val 47 834 PRT Musmusculus 47 Met Ala Pro His Trp Ala Val Trp Leu Leu Ala Ala Gly Leu TrpGly 1 5 10 15 Leu Gly Ile Gly Ala Glu Met Trp Trp Asn Leu Val Pro ArgLys Thr 20 25 30 Val Ser Ser Gly Glu Leu Val Thr Val Val Arg Arg Phe SerGln Thr 35 40 45 Gly Ile Gln Asp Phe Leu Thr Leu Thr Leu Thr Glu His SerGly Leu 50 55 60 Leu Tyr Val Gly Ala Arg Glu Ala Leu Phe Ala Phe Ser ValGlu Ala 65 70 75 80 Leu Glu Leu Gln Gly Ala Ile Ser Trp Glu Ala Pro AlaGlu Lys Lys 85 90 95 Ile Glu Cys Thr Gln Lys Gly Lys Ser Asn Gln Thr GluCys Phe Asn 100 105 110 Phe Ile Arg Phe Leu Gln Pro Tyr Asn Ser Ser HisLeu Tyr Val Cys 115 120 125 Gly Thr Tyr Ala Phe Gln Pro Lys Cys Thr TyrIle Asn Met Leu Thr 130 135 140 Phe Thr Leu Asp Arg Ala Glu Phe Glu AspGly Lys Gly Lys Cys Pro 145 150 155 160 Tyr Asp Pro Ala Lys Gly His ThrGly Leu Leu Val Asp Gly Glu Leu 165 170 175 Tyr Ser Ala Thr Leu Asn AsnPhe Leu Gly Thr Glu Pro Val Ile Leu 180 185 190 Arg Tyr Met Gly Thr HisHis Ser Ile Lys Thr Glu Tyr Leu Ala Phe 195 200 205 Trp Leu Asn Glu ProHis Phe Val Gly Ser Ala Phe Val Pro Glu Ser 210 215 220 Val Gly Ser PheThr Gly Asp Asp Asp Lys Ile Tyr Phe Phe Phe Ser 225 230 235 240 Glu ArgAla Val Glu Tyr Asp Cys Tyr Ser Glu Gln Val Val Ala Arg 245 250 255 ValAla Arg Val Cys Lys Gly Asp Met Gly Gly Ala Arg Thr Leu Gln 260 265 270Lys Lys Trp Thr Thr Phe Leu Lys Ala Arg Leu Val Cys Ser Ala Pro 275 280285 Asp Trp Lys Val Tyr Phe Asn Gln Leu Lys Ala Val His Thr Leu Arg 290295 300 Gly Ala Ser Trp His Asn Thr Thr Phe Phe Gly Val Phe Gln Ala Arg305 310 315 320 Trp Gly Asp Met Asp Leu Ser Ala Val Cys Glu Tyr Gln LeuGlu Gln 325 330 335 Ile Gln Gln Val Phe Glu Gly Pro Tyr Lys Glu Tyr SerGlu Gln Ala 340 345 350 Gln Lys Trp Ala Arg Tyr Thr Asp Pro Val Pro SerPro Arg Pro Gly 355 360 365 Ser Cys Ile Asn Asn Trp His Arg Asp Asn GlyTyr Thr Ser Ser Leu 370 375 380 Glu Leu Pro Asp Asn Thr Leu Asn Phe IleLys Lys His Pro Leu Met 385 390 395 400 Glu Asp Gln Val Lys Pro Arg LeuGly Arg Pro Leu Leu Val Lys Lys 405 410 415 Asn Thr Asn Phe Thr His ValVal Ala Asp Arg Val Pro Gly Leu Asp 420 425 430 Gly Ala Thr Tyr Thr ValLeu Phe Ile Gly Thr Gly Asp Gly Trp Leu 435 440 445 Leu Lys Ala Val SerLeu Gly Pro Trp Ile His Met Val Glu Glu Leu 450 455 460 Gln Val Phe AspGln Glu Pro Val Glu Ser Leu Val Leu Ser Gln Ser 465 470 475 480 Lys LysVal Leu Phe Ala Gly Ser Arg Ser Gln Leu Val Gln Leu Ser 485 490 495 LeuAla Asp Cys Thr Lys Tyr Arg Phe Cys Val Asp Cys Val Leu Ala 500 505 510Arg Asp Pro Tyr Cys Ala Trp Asn Val Asn Thr Ser Arg Cys Val Ala 515 520525 Thr Thr Ser Gly Arg Ser Gly Ser Phe Leu Val Gln His Val Ala Asn 530535 540 Leu Asp Thr Ser Lys Met Cys Asn Gln Tyr Gly Ile Lys Lys Val Arg545 550 555 560 Ser Ile Pro Lys Asn Ile Thr Val Val Ser Gly Thr Asp LeuVal Leu 565 570 575 Pro Cys His Leu Ser Ser Asn Leu Ala His Ala His TrpThr Phe Gly 580 585 590 Ser Gln Asp Leu Pro Ala Glu Gln Pro Gly Ser PheLeu Tyr Asp Thr 595 600 605 Gly Leu Gln Ala Leu Val Val Met Ala Ala GlnSer Arg His Ser Gly 610 615 620 Pro Tyr Arg Cys Tyr Ser Glu Glu Gln GlyThr Arg Leu Ala Ala Glu 625 630 635 640 Ser Tyr Leu Val Ala Val Val AlaGly Ser Ser Val Thr Leu Glu Ala 645 650 655 Arg Ala Pro Leu Glu Asn LeuGly Leu Val Trp Leu Ala Val Val Ala 660 665 670 Leu Gly Ala Val Cys LeuVal Leu Leu Leu Leu Val Leu Ser Leu Arg 675 680 685 Arg Arg Leu Arg GluGlu Leu Glu Lys Gly Ala Lys Ala Ser Glu Arg 690 695 700 Thr Leu Val TyrPro Leu Glu Leu Pro Lys Glu Pro Ala Ser Pro Pro 705 710 715 720 Phe ArgPro Gly Pro Glu Thr Asp Glu Lys Leu Trp Asp Pro Val Gly 725 730 735 TyrTyr Tyr Ser Asp Gly Ser Leu Lys Ile Val Pro Gly His Ala Arg 740 745 750Cys Gln Pro Gly Gly Gly Pro Pro Ser Pro Pro Pro Gly Ile Pro Gly 755 760765 Gln Pro Leu Pro Ser Pro Thr Arg Leu His Leu Gly Gly Gly Arg Asn 770775 780 Ser Asn Ala Asn Gly Tyr Val Arg Leu Gln Leu Gly Gly Glu Asp Arg785 790 795 800 Gly Gly Ser Gly His Pro Leu Pro Glu Leu Ala Asp Glu LeuArg Arg 805 810 815 Lys Leu Gln Gln Arg Gln Pro Leu Pro Asp Ser Asn ProGlu Glu Ser 820 825 830 Ser Val 48 510 PRT Homo sapiens 48 Met Tyr LeuSer Ala Ile Cys Glu Tyr Gln Leu Glu Glu Ile Gln Arg 1 5 10 15 Val PheGlu Gly Pro Tyr Lys Glu Tyr His Glu Glu Ala Gln Lys Trp 20 25 30 Asp ArgTyr Thr Asp Pro Val Pro Ser Pro Arg Pro Gly Ser Cys Ile 35 40 45 Asn AsnTrp His Arg Arg His Gly Tyr Thr Ser Ser Leu Glu Leu Pro 50 55 60 Asp AsnIle Leu Asn Phe Val Lys Lys His Pro Leu Met Glu Glu Gln 65 70 75 80 ValGly Pro Arg Trp Ser Arg Pro Leu Leu Val Lys Lys Gly Thr Asn 85 90 95 PheThr His Leu Val Ala Asp Arg Val Thr Gly Leu Asp Gly Ala Thr 100 105 110Tyr Thr Val Leu Phe Ile Asp Thr Gly Asp Gly Trp Leu Leu Lys Ala 115 120125 Val Ser Leu Gly Pro Trp Val His Leu Ile Glu Glu Leu Gln Leu Phe 130135 140 Asp Gln Glu Pro Met Arg Ser Leu Val Leu Ser Gln Ser Lys Lys Leu145 150 155 160 Leu Phe Ala Gly Ser Arg Ser Gln Leu Val Gln Leu Pro ValAla Asp 165 170 175 Cys Met Lys Tyr Arg Ser Cys Ala Asp Cys Val Leu AlaArg Asp Pro 180 185 190 Tyr Cys Ala Trp Ser Val Asn Thr Ser Arg Cys ValAla Val Gly Gly 195 200 205 His Ser Gly Ser Leu Leu Ile Gln His Val MetThr Ser Asp Thr Ser 210 215 220 Gly Ile Cys Asn Leu Arg Gly Ser Lys LysVal Arg Pro Thr Pro Lys 225 230 235 240 Asn Ile Thr Val Val Ala Gly ThrAsp Leu Val Leu Pro Cys His Leu 245 250 255 Ser Ser Asn Leu Ala His AlaArg Trp Thr Phe Gly Gly Arg Asp Leu 260 265 270 Pro Ala Glu Gln Pro GlySer Phe Leu Tyr Asp Ala Arg Leu Gln Ala 275 280 285 Leu Val Val Met AlaAla Gln Pro Arg His Ala Gly Ala Tyr His Cys 290 295 300 Phe Ser Glu GluGln Gly Ala Arg Leu Ala Ala Glu Gly Tyr Leu Val 305 310 315 320 Ala ValVal Ala Gly Pro Ser Val Thr Leu Glu Ala Arg Ala Pro Leu 325 330 335 GluAsn Leu Gly Leu Val Trp Leu Ala Val Val Ala Leu Gly Ala Val 340 345 350Cys Leu Val Leu Leu Leu Leu Val Leu Ser Leu Arg Arg Arg Leu Arg 355 360365 Glu Glu Leu Glu Lys Gly Ala Lys Ala Thr Glu Arg Thr Leu Val Tyr 370375 380 Pro Leu Glu Leu Pro Lys Glu Pro Thr Ser Pro Pro Phe Arg Pro Cys385 390 395 400 Pro Glu Pro Asp Glu Lys Leu Trp Asp Pro Val Gly Tyr TyrTyr Ser 405 410 415 Asp Gly Ser Leu Lys Ile Val Pro Gly His Ala Arg CysGln Pro Gly 420 425 430 Gly Gly Pro Pro Ser Pro Pro Pro Gly Ile Pro GlyGln Pro Leu Pro 435 440 445 Ser Pro Thr Arg Leu His Leu Gly Gly Gly ArgAsn Ser Asn Ala Asn 450 455 460 Gly Tyr Val Arg Leu Gln Leu Gly Gly GluAsp Arg Gly Gly Leu Gly 465 470 475 480 His Pro Leu Pro Glu Leu Ala AspGlu Leu Arg Arg Lys Leu Gln Gln 485 490 495 Arg Gln Pro Leu Pro Asp SerAsn Pro Glu Glu Ser Ser Val 500 505 510 49 838 PRT Homo sapiens 49 MetTrp Gly Arg Leu Trp Pro Leu Leu Leu Ser Ile Leu Thr Ala Thr 1 5 10 15Ala Val Pro Gly Pro Ser Leu Arg Arg Pro Ser Arg Glu Leu Asp Ala 20 25 30Thr Pro Arg Met Thr Ile Pro Tyr Glu Glu Leu Ser Gly Thr Arg His 35 40 45Phe Lys Gly Gln Ala Gln Asn Tyr Ser Thr Leu Leu Leu Glu Glu Ala 50 55 60Ser Ala Arg Leu Leu Val Gly Ala Arg Gly Ala Leu Phe Ser Leu Ser 65 70 7580 Ala Asn Asp Ile Gly Asp Gly Ala His Lys Glu Ile His Trp Glu Ala 85 9095 Ser Pro Glu Met Gln Ser Lys Cys His Gln Lys Gly Lys Asn Asn Gln 100105 110 Thr Glu Cys Phe Asn His Val Arg Phe Leu Gln Arg Leu Asn Ser Thr115 120 125 His Leu Tyr Ala Cys Gly Thr His Ala Phe Gln Pro Leu Cys AlaAla 130 135 140 Ile Asp Ala Glu Ala Phe Thr Leu Pro Thr Ser Phe Glu GluGly Lys 145 150 155 160 Glu Lys Cys Pro Tyr Asp Pro Ala Arg Gly Phe ThrGly Leu Ile Ile 165 170 175 Asp Gly Gly Leu Tyr Thr Ala Thr Arg Tyr GluPhe Arg Ser Ile Pro 180 185 190 Asp Ile Arg Arg Ser Arg His Pro His SerLeu Arg Thr Glu Glu Thr 195 200 205 Pro Met His Trp Leu Asn Asp Ala GluPhe Val Phe Ser Val Leu Val 210 215 220 Arg Glu Ser Lys Ala Ser Ala ValGly Asp Asp Asp Lys Val Tyr Tyr 225 230 235 240 Phe Phe Thr Glu Arg AlaThr Glu Glu Gly Ser Gly Ser Phe Thr Gln 245 250 255 Ser Arg Ser Ser HisArg Val Ala Arg Val Ala Arg Val Cys Lys Gly 260 265 270 Asp Leu Gly GlyLys Lys Ile Leu Gln Lys Lys Trp Thr Ser Phe Leu 275 280 285 Lys Ala ArgLeu Ile Cys His Ile Pro Leu Tyr Glu Thr Leu Arg Gly 290 295 300 Val CysSer Leu Asp Ala Glu Thr Ser Ser Arg Thr His Phe Tyr Ala 305 310 315 320Ala Phe Thr Leu Ser Thr Gln Trp Lys Thr Leu Glu Ala Ser Ala Ile 325 330335 Cys Arg Tyr Asp Leu Ala Glu Ile Gln Ala Val Phe Ala Gly Pro Tyr 340345 350 Met Glu Tyr Gln Asp Gly Ser Arg Arg Trp Gly Arg Tyr Glu Gly Gly355 360 365 Val Pro Glu Pro Arg Pro Gly Ser Cys Ile Thr Asp Ser Leu ArgSer 370 375 380 Gln Gly Tyr Asn Ser Ser Gln Asp Leu Pro Ser Leu Val LeuAsp Phe 385 390 395 400 Val Lys Leu His Pro Leu Met Ala Arg Pro Val ValPro Thr Arg Gly 405 410 415 Arg Pro Leu Leu Leu Lys Arg Asn Ile Arg TyrThr His Leu Thr Gly 420 425 430 Thr Pro Val Thr Thr Pro Ala Gly Pro ThrTyr Asp Leu Leu Phe Leu 435 440 445 Gly Thr Ala Asp Gly Trp Ile His LysAla Val Val Leu Gly Ser Gly 450 455 460 Met His Ile Ile Glu Glu Thr GlnVal Phe Arg Glu Ser Gln Ser Val 465 470 475 480 Glu Asn Leu Val Ile SerLeu Leu Gln His Ser Leu Tyr Val Gly Ala 485 490 495 Pro Ser Gly Val IleGln Leu Pro Leu Ser Ser Cys Ser Arg Tyr Arg 500 505 510 Ser Cys Tyr AspCys Ile Leu Ala Arg Asp Pro Tyr Cys Gly Trp Asp 515 520 525 Pro Gly ThrHis Ala Cys Ala Ala Ala Thr Thr Ile Ala Asn Arg Thr 530 535 540 Ala LeuIle Gln Asp Ile Glu Arg Gly Asn Arg Gly Cys Glu Ser Ser 545 550 555 560Arg Asp Thr Gly Pro Pro Pro Pro Leu Lys Thr Arg Ser Val Leu Arg 565 570575 Gly Asp Asp Val Leu Leu Pro Cys Asp Gln Pro Ser Asn Leu Ala Arg 580585 590 Ala Leu Trp Leu Leu Asn Gly Ser Met Gly Leu Ser Asp Gly Gln Gly595 600 605 Gly Tyr Arg Val Gly Val Asp Gly Leu Leu Val Thr Asp Ala GlnPro 610 615 620 Glu His Ser Gly Asn Tyr Gly Cys Tyr Ala Glu Glu Asn GlyLeu Arg 625 630 635 640 Thr Leu Leu Ala Ser Tyr Ser Leu Thr Val Arg ProAla Thr Pro Ala 645 650 655 Pro Ala Pro Lys Ala Pro Ala Thr Pro Gly AlaGln Leu Ala Pro Asp 660 665 670 Val Arg Leu Leu Tyr Val Leu Ala Ile AlaAla Leu Gly Gly Leu Cys 675 680 685 Leu Ile Leu Ala Ser Ser Leu Leu TyrVal Ala Cys Leu Arg Glu Gly 690 695 700 Arg Arg Gly Arg Arg Arg Lys TyrSer Leu Gly Arg Ala Ser Arg Ala 705 710 715 720 Gly Gly Ser Ala Val GlnLeu Gln Thr Val Ser Gly Gln Cys Pro Gly 725 730 735 Glu Glu Asp Glu GlyAsp Asp Glu Gly Ala Gly Gly Leu Glu Gly Ser 740 745 750 Cys Leu Gln IleIle Pro Gly Glu Gly Ala Pro Ala Pro Pro Pro Pro 755 760 765 Pro Pro ProPro Pro Pro Ala Glu Leu Thr Asn Gly Leu Val Ala Leu 770 775 780 Pro SerArg Leu Arg Arg Met Asn Gly Asn Ser Tyr Val Leu Leu Arg 785 790 795 800Gln Ser Asn Asn Gly Val Pro Ala Gly Pro Cys Ser Phe Ala Glu Glu 805 810815 Leu Ser Arg Ile Leu Glu Lys Arg Lys His Thr Gln Leu Val Glu Gln 820825 830 Leu Asp Glu Ser Ser Val 835 50 182 PRT Homo sapiens 50 Met LysSer Phe Leu Leu Val Val Asn Ala Leu Ala Leu Thr Leu Pro 1 5 10 15 PheLeu Ala Val Glu Val Gln Asn Gln Lys Gln Pro Ala Cys His Glu 20 25 30 AsnAsp Glu Arg Pro Phe Tyr Gln Lys Thr Ala Pro Tyr Val Pro Met 35 40 45 TyrTyr Val Pro Asn Ser Tyr Pro Tyr Tyr Gly Thr Asn Leu Tyr Gln 50 55 60 ArgArg Pro Ala Ile Ala Ile Asn Asn Pro Tyr Val Pro Arg Thr Tyr 65 70 75 80Tyr Ala Asn Pro Ala Val Val Arg Pro His Ala Gln Ile Pro Gln Arg 85 90 95Gln Tyr Leu Pro Asn Ser His Pro Pro Thr Val Val Arg Arg Pro Asn 100 105110 Leu His Pro Ser Phe Ile Ala Ile Pro Pro Lys Lys Ile Gln Asp Lys 115120 125 Ile Ile Ile Pro Thr Ile Asn Thr Ile Ala Thr Val Glu Pro Thr Pro130 135 140 Ala Pro Ala Thr Glu Pro Thr Val Asp Ser Val Val Thr Pro GluAla 145 150 155 160 Phe Ser Glu Ser Ile Ile Thr Ser Thr Pro Glu Thr ThrThr Val Ala 165 170 175 Val Thr Pro Pro Thr Ala 180 51 182 PRT Homosapiens 51 Met Lys Ser Phe Leu Leu Val Val Asn Ala Leu Ala Leu Thr LeuPro 1 5 10 15 Phe Leu Ala Val Glu Val Gln Asn Gln Lys Gln Pro Ala CysHis Glu 20 25 30 Asn Asp Glu Arg Pro Phe Tyr Gln Lys Thr Ala Pro Tyr ValPro Met 35 40 45 Tyr Tyr Val Pro Asn Ser Tyr Pro Tyr Tyr Gly Thr Asn LeuTyr Gln 50 55 60 Arg Arg Pro Ala Ile Ala Ile Asn Asn Pro Tyr Val Pro ArgThr Tyr 65 70 75 80 Tyr Ala Asn Pro Ala Val Val Arg Pro His Ala Gln IlePro Gln Arg 85 90 95 Gln Tyr Leu Pro Asn Ser His Pro Pro Thr Val Val ArgLeu Pro Asn 100 105 110 Leu His Pro Ser Phe Ile Ala Ile Pro Pro Lys LysIle Gln Asp Lys 115 120 125 Ile Ile Ile Pro Thr Ile Asn Thr Ile Ala ThrVal Glu Pro Thr Pro 130 135 140 Ala Pro Ala Thr Glu Pro Thr Val Asp SerVal Val Thr Pro Glu Ala 145 150 155 160 Phe Ser Glu Ser Ile Ile Thr SerThr Pro Glu Thr Thr Thr Val Ala 165 170 175 Val Thr Pro Pro Thr Ala 18052 182 PRT Homo sapiens 52 Met Lys Ser Phe Leu Leu Val Val Asn Ala LeuAla Leu Thr Leu Pro 1 5 10 15 Phe Leu Ala Val Glu Val Gln Asn Gln LysGln Pro Ala Cys His Glu 20 25 30 Asn Asp Glu Arg Pro Phe Tyr Gln Lys ThrAla Pro Tyr Val Pro Met 35 40 45 Tyr Tyr Val Pro Asn Ser Tyr Pro Tyr TyrGly Thr Asn Leu Tyr Gln 50 55 60 Arg Arg Pro Ala Ile Ala Ile Asn Asn ProTyr Val Pro Arg Thr Tyr 65 70 75 80 Tyr Ala Asn Pro Ala Val Val Arg ProHis Ala Gln Ile Pro Gln Arg 85 90 95 Gln Tyr Leu Pro Asn Ser His Pro ProThr Val Val Arg Arg Pro Asn 100 105 110 Leu His Pro Ser Phe Ile Ala IlePro Pro Lys Lys Ile Gln Asp Lys 115 120 125 Ile Ile Ile Pro Thr Ile AsnThr Ile Ala Thr Val Glu Pro Thr Pro 130 135 140 Thr Pro Ala Thr Glu ProThr Val Asp Ser Val Val Thr Pro Glu Ala 145 150 155 160 Phe Ser Glu SerIle Ile Thr Ser Thr Pro Glu Thr Thr Thr Val Ala 165 170 175 Val Thr ProPro Thr Ala 180 53 182 PRT Homo sapiens VARIANT (19)..(29) Wherein Xaais any amino acid/ 53 Met Lys Ser Phe Leu Leu Val Val Asn Ala Leu AlaLeu Thr Leu Pro 1 5 10 15 Phe Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa XaaXaa Xaa Cys His Glu 20 25 30 Asn Asp Glu Arg Pro Phe Tyr Gln Lys Thr AlaPro Tyr Val Pro Met 35 40 45 Tyr Tyr Val Pro Asn Ser Tyr Pro Tyr Tyr GlyThr Asn Leu Tyr Gln 50 55 60 Arg Arg Pro Ala Ile Ala Ile Asn Asn Pro TyrVal Pro Arg Thr Tyr 65 70 75 80 Tyr Ala Asn Pro Ala Val Val Arg Pro HisAla Gln Ile Pro Gln Arg 85 90 95 Gln Tyr Leu Pro Asn Ser His Pro Pro ThrVal Val Arg Arg Pro Asn 100 105 110 Leu His Pro Ser Phe Ile Ala Ile ProPro Lys Lys Ile Gln Asp Lys 115 120 125 Ile Ile Ile Pro Thr Ile Asn ThrIle Ala Thr Val Glu Pro Thr Pro 130 135 140 Ala Pro Ala Thr Glu Pro ThrVal Asp Ser Val Val Thr Pro Glu Ala 145 150 155 160 Phe Ser Glu Ser IleIle Thr Ser Thr Pro Glu Thr Thr Thr Val Ala 165 170 175 Val Thr Pro ProThr Ala 180 54 182 PRT Homo sapiens 54 Met Lys Ser Phe Phe Leu Val ValThr Ile Leu Ala Leu Thr Leu Pro 1 5 10 15 Phe Leu Gly Ala Glu Val GlnAsn Gln Glu Gln Pro Thr Cys Phe Glu 20 25 30 Lys Val Glu Arg Leu Leu AsnGlu Lys Thr Val Lys Tyr Phe Pro Ile 35 40 45 Gln Phe Val Gln Ser Arg TyrPro Ser Tyr Gly Ile Asn Tyr Tyr Gln 50 55 60 His Arg Leu Ala Val Pro IleAsn Asn Gln Phe Ile Pro Tyr Pro Asn 65 70 75 80 Tyr Ala Lys Pro Val AlaIle Arg Leu His Ala Gln Ile Pro Gln Cys 85 90 95 Gln Ala Leu Pro Asn IleAsp Pro Pro Thr Val Glu Arg Arg Pro Arg 100 105 110 Pro Arg Pro Ser PheIle Ala Ile Pro Pro Lys Lys Thr Gln Asp Lys 115 120 125 Thr Val Asn ProAla Ile Asn Thr Val Ala Thr Val Glu Pro Pro Val 130 135 140 Ile Pro ThrAla Glu Pro Ala Val Asn Thr Val Val Ile Ala Glu Ala 145 150 155 160 SerSer Glu Phe Ile Thr Thr Ser Thr Pro Glu Thr Thr Thr Val Gln 165 170 175Ile Thr Ser Thr Glu Ile 180 55 458 PRT Homo sapiens 55 Met Ala Gly SerPro Ser Arg Ala Ala Gly Arg Arg Leu Gln Leu Pro 1 5 10 15 Leu Leu CysLeu Phe Leu Gln Gly Ala Thr Ala Val Leu Phe Ala Val 20 25 30 Phe Val ArgTyr Asn His Lys Thr Asp Ala Ala Leu Trp His Arg Ser 35 40 45 Asn His SerAsn Ala Asp Asn Glu Phe Tyr Phe Arg Tyr Pro Ser Phe 50 55 60 Gln Asp ValHis Ala Met Val Phe Val Gly Phe Gly Phe Leu Met Val 65 70 75 80 Phe LeuGln Arg Tyr Gly Phe Ser Ser Val Gly Phe Thr Phe Leu Leu 85 90 95 Ala AlaPhe Ala Leu Gln Trp Ser Thr Leu Val Gln Gly Phe Leu His 100 105 110 SerPhe His Gly Gly His Ile His Val Gly Val Glu Ser Met Ile Asn 115 120 125Ala Asp Phe Cys Ala Gly Ala Val Leu Ile Ser Phe Gly Ala Val Leu 130 135140 Gly Lys Thr Gly Pro Thr Gln Leu Leu Leu Met Ala Leu Leu Glu Val 145150 155 160 Val Leu Phe Gly Ile Asn Glu Phe Val Leu Leu His Leu Leu GlyVal 165 170 175 Arg Asp Ala Gly Gly Ser Met Thr Ile His Thr Phe Gly AlaTyr Phe 180 185 190 Gly Leu Val Leu Ser Arg Val Leu Tyr Arg Pro Gln LeuGlu Lys Ser 195 200 205 Lys His Arg Gln Gly Ser Val Tyr His Ser Asp LeuPhe Ala Met Ile 210 215 220 Gly Thr Ile Phe Leu Trp Ile Phe Trp Pro SerPhe Asn Ala Ala Leu 225 230 235 240 Thr Ala Leu Gly Ala Gly Gln His ArgThr Ala Leu Asn Thr Tyr Tyr 245 250 255 Ser Leu Ala Ala Ser Thr Leu GlyThr Phe Ala Leu Ser Ala Leu Val 260 265 270 Gly Glu Asp Gly Arg Leu AspMet Val His Ile Gln Asn Ala Ala Leu 275 280 285 Ala Gly Gly Val Val ValGly Thr Ser Ser Glu Met Met Leu Thr Pro 290 295 300 Phe Gly Ala Leu AlaAla Gly Phe Leu Ala Gly Thr Val Ser Thr Leu 305 310 315 320 Gly Tyr LysPhe Phe Thr Pro Ile Leu Glu Ser Lys Phe Lys Val Gln 325 330 335 Asp ThrCys Gly Val His Asn Leu His Gly Met Pro Gly Val Leu Gly 340 345 350 AlaLeu Leu Gly Val Leu Val Ala Gly Leu Ala Thr His Glu Ala Tyr 355 360 365Gly Asp Gly Leu Glu Ser Val Phe Pro Leu Ile Ala Glu Gly Gln Arg 370 375380 Ser Ala Thr Ser Gln Ala Met His Gln Leu Phe Gly Leu Phe Val Thr 385390 395 400 Leu Met Phe Ala Ser Val Gly Gly Gly Leu Gly Gly Leu Leu LeuLys 405 410 415 Leu Pro Phe Leu Asp Ser Pro Pro Asp Ser Gln His Tyr GluAsp Gln 420 425 430 Val His Trp Gln Val Pro Gly Glu His Glu Asp Lys AlaGln Arg Pro 435 440 445 Leu Arg Val Glu Glu Ala Asp Thr Gln Ala 450 45556 458 PRT Pan troglodytes 56 Met Ala Gly Ser Pro Ser Arg Ala Ala GlyArg Arg Leu Gln Leu Pro 1 5 10 15 Leu Leu Cys Leu Phe Leu Gln Gly AlaThr Ala Val Leu Phe Ala Val 20 25 30 Phe Val Arg Tyr Asn His Lys Thr AspAla Ala Leu Trp His Arg Ser 35 40 45 Asn His Ser Asn Ala Asp Asn Glu PheTyr Phe Arg Tyr Pro Ser Phe 50 55 60 Gln Asp Val His Ala Met Val Phe ValGly Phe Gly Phe Leu Met Val 65 70 75 80 Phe Leu Gln Arg Tyr Gly Phe SerSer Val Gly Phe Thr Phe Leu Leu 85 90 95 Ala Ala Phe Ala Leu Gln Trp SerThr Leu Val Gln Gly Phe Leu His 100 105 110 Ser Phe His Gly Gly His IleHis Val Gly Val Glu Ser Met Ile Asn 115 120 125 Ala Asp Phe Cys Ala GlyAla Val Leu Ile Ser Phe Gly Ala Val Leu 130 135 140 Gly Lys Thr Gly ProAla Gln Leu Leu Leu Met Ala Leu Leu Glu Val 145 150 155 160 Val Leu PheGly Ile Asn Glu Phe Val Leu Leu His Leu Leu Gly Val 165 170 175 Arg AspAla Gly Gly Ser Met Thr Ile His Thr Phe Gly Ala Tyr Phe 180 185 190 GlyLeu Val Leu Ser Arg Val Leu Tyr Arg Pro Gln Leu Glu Lys Ser 195 200 205Lys His Arg Gln Gly Ser Val Tyr His Ser Asp Leu Phe Ala Met Ile 210 215220 Gly Thr Ile Phe Leu Trp Ile Phe Trp Pro Ser Phe Asn Ala Ala Leu 225230 235 240 Thr Ala Leu Gly Ala Gly Gln His Arg Thr Ala Leu Asn Thr TyrTyr 245 250 255 Ser Leu Ala Ala Ser Thr Leu Gly Thr Phe Ala Leu Ser AlaLeu Val 260 265 270 Gly Glu Asp Gly Arg Leu Asp Met Val His Ile Gln AsnAla Ala Leu 275 280 285 Ala Gly Gly Val Val Val Gly Thr Ser Ser Glu MetMet Leu Thr Pro 290 295 300 Phe Gly Ala Leu Thr Ala Gly Phe Leu Ala GlyThr Val Ser Thr Leu 305 310 315 320 Gly Tyr Lys Phe Phe Arg Pro Ile LeuGlu Ser Lys Phe Lys Val Gln 325 330 335 Asp Thr Cys Gly Val His Asn LeuHis Gly Met Pro Gly Val Leu Gly 340 345 350 Ala Leu Leu Gly Val Leu ValAla Gly Leu Ala Thr His Glu Ala Tyr 355 360 365 Gly Asp Gly Leu Glu SerVal Phe Pro Leu Ile Ala Glu Gly Gln Arg 370 375 380 Ser Ala Thr Ser GlnAla Met His Gln Leu Phe Gly Leu Phe Val Thr 385 390 395 400 Leu Met PheAla Ser Val Gly Gly Gly Leu Gly Gly Leu Leu Leu Lys 405 410 415 Leu ProPhe Leu Asp Ser Pro Pro Asp Ser Gln Cys Tyr Glu Asp Gln 420 425 430 ValHis Trp Gln Val Pro Gly Glu His Glu Asp Lys Ala Gln Arg Pro 435 440 445Leu Arg Val Glu Glu Ala Asp Thr Gln Ala 450 455 57 458 PRT Sus scrofa 57Met Ala Gly Ser Ser Arg Arg Ala Gly Gly Arg Arg Leu Gln Leu Pro 1 5 1015 Leu Leu Cys Leu Leu Leu Gln Gly Ala Thr Ala Ile Leu Phe Ala Val 20 2530 Phe Val Arg Tyr Asn His Glu Thr Asp Ala Ala Leu Trp His Trp Gly 35 4045 Asn His Ser Asn Pro Asp Asn Glu Phe Tyr Phe Arg Tyr Pro Ser Phe 50 5560 Gln Asp Val His Thr Met Ile Phe Val Gly Phe Gly Phe Leu Met Ala 65 7075 80 Phe Leu Gln Arg Tyr Gly Phe Ser Ser Val Gly Phe Thr Phe Leu Leu 8590 95 Ala Ala Phe Ala Leu Gln Trp Ser Thr Leu Val Gln Gly Phe Leu His100 105 110 Thr Phe His Gly Gly His Ile His Ile Gly Val Glu Ser Met IleAsn 115 120 125 Ala Asp Phe Cys Ala Gly Ala Val Leu Ile Ser Phe Gly AlaIle Leu 130 135 140 Gly Lys Thr Gly Pro Ala Gln Leu Leu Leu Met Ala LeuLeu Glu Val 145 150 155 160 Val Leu Phe Gly Leu Asn Glu Phe Val Leu LeuSer Leu Leu Gly Val 165 170 175 Lys Asp Ala Gly Gly Ser Met Thr Ile HisThr Phe Gly Ala Tyr Phe 180 185 190 Gly Leu Val Leu Ser Arg Val Leu TyrArg Pro Gln Leu Glu Lys Ser 195 200 205 Lys His Arg Gln Ser Ser Val TyrHis Ser Asp Leu Phe Ala Met Ile 210 215 220 Gly Thr Ile Phe Leu Trp IlePhe Trp Pro Ser Phe Asn Ser Ala Pro 225 230 235 240 Thr Pro Leu Gly AspGly Gln His Arg Thr Ala Leu Asn Thr Tyr Tyr 245 250 255 Ser Leu Thr AlaSer Thr Leu Ser Thr Phe Ala Leu Ser Ala Leu Val 260 265 270 Gly Arg AspGly Arg Leu Asp Met Val His Val Gln Asn Ala Ala Leu 275 280 285 Ala GlyGly Val Val Val Gly Thr Ser Ala Glu Met Met Leu Thr Pro 290 295 300 PheGly Ala Leu Ala Ala Gly Phe Leu Ala Gly Thr Val Ser Thr Leu 305 310 315320 Gly Phe Lys Phe Phe Thr Pro Ile Leu Glu Ser Lys Phe Lys Ile Gln 325330 335 Asp Thr Cys Gly Val His Asn Leu His Gly Met Pro Gly Val Leu Gly340 345 350 Ala Leu Leu Gly Val Leu Val Ala Gly Leu Ala Thr His Asp SerTyr 355 360 365 Gly Glu Gly Leu Glu Ser Val Phe Pro Leu Ile Ala Glu GlyGln Arg 370 375 380 Ser Ser Thr Ser Gln Ala Leu His Gln Leu Phe Gly LeuPhe Val Thr 385 390 395 400 Leu Ile Phe Ala Ser Val Gly Gly Gly Leu GlyGly Leu Leu Leu Arg 405 410 415 Leu Pro Phe Leu Asp Ser Pro Pro Asp SerGln Cys Tyr Glu Asp Gln 420 425 430 Ile Tyr Trp Glu Val Pro Glu Glu HisAla Asp Leu Ala Gln Gly Ser 435 440 445 Leu Arg Pro Glu Glu Pro Asp ThrGln Ala 450 455 58 455 PRT Mus musculus 58 Met Ala Arg Val Pro Arg HisArg Arg Leu Val Leu Pro Leu Leu Cys 1 5 10 15 Leu Leu Phe Gln Gly AlaThr Ala Leu Leu Phe Ala Ile Phe Val Arg 20 25 30 Tyr Asn His Glu Thr AspAla Ala Leu Trp His Trp Gly Asn His Ser 35 40 45 Asn Val Asp Asn Glu PheTyr Phe Arg Tyr Pro Ser Phe Gln Asp Val 50 55 60 His Val Met Val Phe ValGly Phe Gly Phe Leu Met Val Phe Leu Gln 65 70 75 80 Arg Tyr Gly Phe SerSer Val Gly Phe Thr Phe Leu Val Ala Ser Leu 85 90 95 Thr Leu Gln Trp AlaThr Leu Leu Gln Gly Phe Leu His Ser Phe His 100 105 110 Gly Gly His IleHis Val Gly Val Glu Ser Leu Ile Asn Ala Asp Phe 115 120 125 Cys Ala GlyAla Val Leu Ile Ser Phe Gly Ala Val Leu Gly Lys Thr 130 135 140 Gly ProAla Gln Leu Leu Leu Met Ala Leu Leu Glu Ala Val Leu Phe 145 150 155 160Ser Val Asn Glu Phe Ile Leu Leu Ser Leu Leu Gly Val Arg Asp Ala 165 170175 Gly Gly Ser Met Thr Ile His Thr Phe Gly Ala Tyr Phe Gly Leu Phe 180185 190 Leu Ser Arg Val Leu Tyr Arg Ser Gln Leu Glu Lys Ser Arg His Arg195 200 205 Gln Ser Ser Val Tyr Asn Ser Asp Leu Phe Ala Met Ile Gly ThrIle 210 215 220 Phe Leu Trp Val Phe Trp Pro Ser Phe Asn Ser Ala Pro ThrAla Leu 225 230 235 240 Gly Asp Gly Gln His Arg Thr Val Val Asn Thr TyrTyr Ser Leu Thr 245 250 255 Ala Ser Thr Leu Ser Thr Phe Ala Leu Ser AlaLeu Val Ser Gly Asp 260 265 270 Gly Arg Leu Asp Met Val His Val Gln AsnAla Ala Leu Ala Gly Gly 275 280 285 Val Val Val Gly Thr Ser Ser Glu MetMet Leu Thr Pro Phe Gly Ala 290 295 300 Leu Ala Ala Gly Phe Leu Ala GlyThr Val Ser Thr Leu Gly Tyr Lys 305 310 315 320 Phe Phe Thr Pro Ile LeuGlu Ser Arg Phe Lys Leu Gln Asp Thr Cys 325 330 335 Gly Val His Asn LeuHis Gly Met Pro Gly Val Leu Gly Ala Ile Leu 340 345 350 Gly Val Val ValAla Ala Leu Ala Thr His Glu Ala Tyr Gly Asp Gly 355 360 365 Leu Gln SerVal Phe Pro Leu Ile Ala Lys Gly Gln Arg Ser Ala Thr 370 375 380 Ser GlnAla Val Tyr Gln Leu Phe Gly Met Phe Val Thr Leu Val Phe 385 390 395 400Ala Ser Val Gly Gly Ser Leu Gly Gly Leu Leu Leu Arg Leu Pro Phe 405 410415 Leu Asp Ser Pro Pro Asp Ser Gln Cys Phe Glu Asp Gln Val Tyr Trp 420425 430 Glu Val Pro Gly Glu Gln Glu Thr Glu Thr Gln Arg Pro Leu Arg Gly435 440 445 Gly Glu Ser Asp Thr Arg Ala 450 455 59 458 PRT Orycctolaguscuniculus 59 Met Ala Lys Ser Pro Arg Arg Val Ala Gly Arg Arg Leu Leu LeuPro 1 5 10 15 Leu Leu Cys Leu Phe Phe Gln Gly Ala Thr Ala Ile Leu PheAla Ile 20 25 30 Phe Val Arg Tyr Asp Gln Gln Thr Asp Ala Ala Leu Trp HisGly Gly 35 40 45 Asn His Ser Asn Ala Asp Asn Glu Phe Tyr Phe Arg Tyr ProSer Phe 50 55 60 Gln Asp Val His Ala Met Val Phe Val Gly Phe Gly Phe LeuMet Val 65 70 75 80 Phe Leu Gln Arg Tyr Gly Tyr Ser Ser Leu Gly Phe ThrPhe Leu Leu 85 90 95 Gly Ala Phe Ala Leu Gln Trp Ala Thr Leu Val Gln GlyPhe Leu His 100 105 110 Ser Phe His Gly Gly His Ile His Val Gly Met GluSer Leu Ile Asn 115 120 125 Ala Asp Phe Cys Ala Gly Ala Val Leu Ile SerPhe Gly Ala Val Leu 130 135 140 Gly Lys Thr Gly Pro Ala Gln Leu Leu LeuMet Ala Leu Leu Glu Val 145 150 155 160 Ala Leu Phe Gly Leu Asn Glu PheVal Leu Leu Cys Leu Leu Gly Val 165 170 175 Arg Asp Ala Gly Gly Ser MetThr Ile His Thr Phe Gly Ala Tyr Phe 180 185 190 Gly Leu Val Leu Ser ArgVal Leu Tyr Arg Pro His Leu Glu Lys Ser 195 200 205 Gln His Arg Gln GlySer Val Tyr His Ser Asp Leu Phe Ala Met Ile 210 215 220 Gly Thr Ile PheLeu Trp Ile Phe Trp Pro Ser Phe Asn Ser Ala Leu 225 230 235 240 Thr SerArg Gly Asp Gly Gln Pro Arg Thr Ala Leu Asn Thr Tyr Tyr 245 250 255 SerLeu Thr Ala Ser Thr Leu Ser Thr Phe Ala Leu Ser Ala Leu Val 260 265 270Gly Lys Asp Gly Arg Leu Asp Met Val His Val Gln Asn Ala Ala Leu 275 280285 Ala Gly Gly Val Val Val Gly Thr Ala Ser Glu Met Met Leu Thr Pro 290295 300 Phe Gly Ala Leu Ala Ala Gly Cys Leu Ala Gly Ala Ile Ser Thr Leu305 310 315 320 Gly Tyr Lys Phe Phe Thr Pro Ile Leu Glu Ser Lys Leu LysIle Gln 325 330 335 Asp Thr Cys Gly Val His Asn Leu His Gly Met Pro GlyVal Leu Gly 340 345 350 Ala Leu Leu Gly Ala Leu Met Thr Gly Leu Thr ThrHis Glu Ala Tyr 355 360 365 Gly Asp Gly Leu Gln Ser Val Phe Pro Leu IleAla Glu Gly Gln Arg 370 375 380 Ser Ala Thr Ser Gln Ala Ile Tyr Gln LeuPhe Gly Leu Ser Val Thr 385 390 395 400 Leu Leu Phe Ala Ser Ala Gly GlyVal Leu Gly Gly Leu Leu Leu Lys 405 410 415 Leu Pro Phe Leu Asp Ala ProPro Asp Ser Gln Cys Tyr Glu Asp Gln 420 425 430 Met Cys Trp Glu Val ProGly Glu His Gly Tyr Glu Ala Gln Glu Ala 435 440 445 Leu Arg Val Glu GluPro Asp Thr Glu Ala 450 455 60 485 PRT Rattus norvegicus 60 Met Ser ValPro Leu Leu Lys Ile Gly Val Val Leu Ser Thr Met Ala 1 5 10 15 Met IleThr Asn Trp Met Ser Gln Thr Leu Pro Ser Leu Val Gly Leu 20 25 30 Asn ThrThr Arg Leu Ser Ala Ala Ser Gly Gly Thr Leu Asp Arg Ser 35 40 45 Thr GlyVal Leu Pro Thr Asn Pro Glu Glu Ser Trp Gln Val Tyr Ser 50 55 60 Ser AlaGln Asp Ser Glu Gly Arg Cys Ile Cys Thr Val Val Ala Pro 65 70 75 80 GlnGln Thr Met Cys Ser Arg Asp Ala Arg Thr Lys Gln Leu Arg Gln 85 90 95 LeuLeu Glu Lys Val Gln Asn Met Ser Gln Ser Ile Glu Val Leu Asp 100 105 110Arg Arg Thr Gln Arg Asp Leu Gln Tyr Val Glu Lys Met Glu Asn Gln 115 120125 Met Lys Gly Leu Glu Ser Lys Phe Arg Gln Val Glu Glu Ser His Lys 130135 140 Gln His Leu Ala Arg Gln Phe Lys Ala Ile Lys Ala Lys Met Asp Glu145 150 155 160 Leu Arg Pro Leu Ile Pro Val Leu Glu Glu Tyr Lys Ala AspAla Lys 165 170 175 Leu Val Leu Gln Phe Lys Glu Glu Val Gln Asn Leu ThrSer Val Leu 180 185 190 Asn Glu Leu Gln Glu Glu Ile Gly Ala Tyr Asp TyrAsp Glu Leu Gln 195 200 205 Ser Arg Val Ser Asn Leu Glu Glu Arg Leu ArgAla Cys Met Gln Lys 210 215 220 Leu Ala Cys Gly Lys Leu Thr Gly Ile SerAsp Pro Val Thr Val Lys 225 230 235 240 Thr Ser Gly Ser Arg Phe Gly SerTrp Met Thr Asp Pro Leu Ala Pro 245 250 255 Glu Gly Asp Asn Arg Val TrpTyr Met Asp Gly Tyr His Asn Asn Arg 260 265 270 Phe Val Arg Glu Tyr LysSer Met Val Asp Phe Met Asn Thr Asp Asn 275 280 285 Phe Thr Ser His ArgLeu Pro His Pro Trp Ser Gly Thr Gly Gln Val 290 295 300 Val Tyr Asn GlySer Ile Tyr Phe Asn Lys Phe Gln Ser His Ile Ile 305 310 315 320 Ile ArgPhe Asp Leu Lys Thr Glu Thr Ile Leu Lys Thr Arg Ser Leu 325 330 335 AspTyr Ala Gly Tyr Asn Asn Met Tyr His Tyr Ala Trp Gly Gly His 340 345 350Ser Asp Ile Asp Leu Met Val Asp Glu Asn Gly Leu Trp Ala Val Tyr 355 360365 Ala Thr Asn Gln Asn Ala Gly Asn Ile Val Ile Ser Lys Leu Asp Pro 370375 380 Val Ser Leu Gln Ile Leu Gln Thr Trp Asn Thr Ser Tyr Pro Lys Arg385 390 395 400 Ser Ala Gly Glu Ala Phe Ile Ile Cys Gly Thr Leu Tyr ValThr Asn 405 410 415 Gly Tyr Ser Gly Gly Thr Lys Val His Tyr Ala Tyr GlnThr Asn Ala 420 425 430 Ser Thr Tyr Glu Tyr Ile Asp Ile Pro Phe Gln AsnLys Tyr Ser His 435 440 445 Ile Ser Met Leu Asp Tyr Asn Pro Lys Asp ArgAla Leu Tyr Ala Trp 450 455 460 Asn Asn Gly His Gln Thr Leu Tyr Asn ValThr Leu Phe His Val Ile 465 470 475 480 Arg Ser Asp Glu Leu 485 61 485PRT Gallus gallus 61 Met Ser Val Pro Leu Leu Lys Ile Gly Val Val Leu SerThr Met Ala 1 5 10 15 Met Ile Thr Asn Trp Met Ser Gln Thr Leu Pro SerLeu Val Gly Leu 20 25 30 Asn Thr Thr Lys Leu Thr Ala Ala Ser Gly Gly ThrLeu Asp Arg Ser 35 40 45 Thr Gly Val Leu Pro Thr Asn Pro Glu Glu Ser TrpGln Val Tyr Ser 50 55 60 Ser Ala Gln Asp Ser Glu Gly Arg Cys Ile Cys ThrVal Val Ala Pro 65 70 75 80 Gln Gln Thr Met Cys Ser Arg Asp Ala Arg ThrLys Gln Leu Arg Gln 85 90 95 Leu Leu Glu Lys Val Gln Asn Met Ser Gln SerIle Glu Val Leu Asp 100 105 110 Arg Arg Thr Gln Arg Asp Leu Gln Tyr ValGlu Lys Met Glu Asn Gln 115 120 125 Met Arg Gly Leu Glu Ser Lys Phe LysGln Val Glu Glu Ser His Lys 130 135 140 Gln His Leu Ala Arg Gln Phe LysAla Ile Lys Ala Lys Met Glu Glu 145 150 155 160 Leu Arg Pro Leu Ile ProVal Leu Glu Glu Tyr Lys Ala Asp Ala Lys 165 170 175 Leu Val Leu Gln PheLys Glu Glu Val Gln Asn Leu Thr Ser Val Leu 180 185 190 Asn Glu Leu GlnGlu Glu Ile Gly Ala Tyr Asp Tyr Glu Glu Leu Gln 195 200 205 Asn Arg ValSer Asn Leu Glu Glu Arg Leu Arg Ala Cys Met Gln Lys 210 215 220 Leu AlaCys Gly Lys Leu Thr Gly Ile Ser Asp Pro Ile Thr Ile Lys 225 230 235 240Thr Ser Gly Ser Arg Phe Gly Ser Trp Met Thr Asp Pro Leu Ala Pro 245 250255 Glu Gly Glu Asn Lys Val Trp Tyr Met Asp Ser Tyr His Asn Asn Arg 260265 270 Phe Val Arg Glu Tyr Lys Ser Met Ala Asp Phe Met Asn Thr Asp Asn275 280 285 Phe Thr Ser His Arg Leu Pro His Pro Trp Ser Gly Thr Gly GlnVal 290 295 300 Val Tyr Asn Gly Ser Ile Tyr Phe Asn Lys Tyr Gln Ser HisIle Ile 305 310 315 320 Ile Arg Phe Asp Leu Lys Thr Glu Thr Ile Leu LysThr Arg Ser Leu 325 330 335 Asp Tyr Ala Gly Tyr Asn Asn Met Tyr His TyrAla Trp Gly Gly His 340 345 350 Ser Asp Ile Asp Leu Met Val Asp Glu AsnGly Leu Trp Ala Val Tyr 355 360 365 Ala Thr Asn Gln Asn Ala Gly Asn IleVal Ile Ser Lys Leu Asp Pro 370 375 380 Asn Thr Leu Gln Ser Leu Gln ThrTrp Asn Thr Ser Tyr Pro Lys Arg 385 390 395 400 Ser Ala Gly Glu Ala PheIle Ile Cys Gly Thr Leu Tyr Val Thr Asn 405 410 415 Gly Tyr Ser Gly GlyThr Lys Val His Tyr Ala Tyr Gln Thr Asn Ala 420 425 430 Ser Thr Tyr GluTyr Ile Asp Ile Pro Phe Gln Asn Lys Tyr Ser His 435 440 445 Ile Ser MetLeu Asp Tyr Asn Pro Lys Asp Arg Ala Leu Tyr Ala Trp 450 455 460 Asn AsnGly His Gln Ile Leu Tyr Asn Val Thr Leu Phe His Val Ile 465 470 475 480Arg Ser Asp Glu Leu 485 62 485 PRT Mus musculus 62 Met Ser Val Pro LeuLeu Lys Ile Gly Val Val Leu Ser Thr Met Ala 1 5 10 15 Met Ile Thr AsnTrp Met Ser Gln Thr Leu Pro Ser Leu Val Gly Leu 20 25 30 Asn Thr Thr ArgLeu Ser Ala Ala Ser Gly Gly Thr Leu Asp Arg Ser 35 40 45 Thr Gly Val LeuPro Thr Asn Pro Glu Glu Ser Trp Gln Val Tyr Ser 50 55 60 Ser Ala Gln AspSer Glu Gly Arg Cys Ile Cys Thr Val Val Ala Pro 65 70 75 80 Gln Gln ThrMet Cys Ser Arg Asp Ala Arg Thr Lys Gln Leu Arg Gln 85 90 95 Leu Leu GluLys Val Gln Asn Met Ser Gln Ser Ile Glu Val Leu Asp 100 105 110 Arg ArgThr Gln Arg Asp Leu Gln Tyr Val Glu Lys Met Glu Asn Gln 115 120 125 MetLys Gly Leu Glu Thr Lys Phe Lys Gln Val Glu Glu Ser His Lys 130 135 140Gln His Leu Ala Arg Gln Phe Lys Ala Ile Lys Ala Lys Met Asp Glu 145 150155 160 Leu Arg Pro Leu Ile Pro Val Leu Glu Glu Tyr Lys Ala Asp Ala Lys165 170 175 Leu Val Leu Gln Phe Lys Glu Glu Val Gln Asn Leu Thr Ser ValLeu 180 185 190 Asn Glu Leu Gln Glu Glu Ile Gly Ala Tyr Asp Tyr Asp GluLeu Gln 195 200 205 Ser Arg Val Ser Asn Leu Glu Glu Arg Leu Arg Ala CysMet Gln Lys 210 215 220 Leu Ala Cys Gly Lys Leu Thr Gly Ile Ser Asp ProVal Thr Val Lys 225 230 235 240 Thr Ser Gly Ser Arg Phe Gly Ser Trp MetThr Asp Pro Leu Ala Pro 245 250 255 Glu Gly Asp Asn Arg Val Trp Tyr MetAsp Gly Tyr His Asn Asn Arg 260 265 270 Phe Val Arg Glu Tyr Lys Ser MetVal Asp Phe Met Asn Thr Asp Asn 275 280 285 Phe Thr Ser His Arg Leu ProHis Pro Trp Ser Gly Thr Gly Gln Val 290 295 300 Val Tyr Asn Gly Ser IleTyr Phe Asn Lys Phe Gln Ser His Ile Ile 305 310 315 320 Ile Arg Phe AspLeu Lys Thr Glu Ala Ile Leu Lys Thr Arg Ser Leu 325 330 335 Asp Tyr AlaGly Tyr Asn Asn Met Tyr His Tyr Ala Trp Gly Gly His 340 345 350 Ser AspIle Asp Leu Met Val Asp Glu Asn Gly Leu Trp Ala Val Tyr 355 360 365 AlaThr Asn Gln Asn Ala Gly Asn Ile Val Ile Ser Lys Leu Asp Pro 370 375 380Val Ser Leu Gln Ile Leu Gln Thr Trp Asn Thr Ser Tyr Pro Lys Arg 385 390395 400 Ser Ala Gly Glu Ala Phe Ile Ile Cys Gly Thr Leu Tyr Val Thr Asn405 410 415 Gly Tyr Ser Gly Gly Thr Lys Val His Tyr Ala Tyr Gln Thr AsnAla 420 425 430 Ser Thr Tyr Glu Tyr Ile Asp Ile Pro Phe Gln Asn Lys TyrSer His 435 440 445 Ile Ser Met Leu Asp Tyr Asn Pro Lys Asp Arg Ala LeuTyr Ala Trp 450 455 460 Asn Asn Gly His Gln Thr Leu Tyr Asn Val Thr LeuPhe His Val Ile 465 470 475 480 Arg Ser Asp Glu Leu 485 63 457 PRTGallus gallus 63 Met Gln Pro Ala Ser Lys Leu Leu Thr Leu Phe Phe Leu IleLeu Met 1 5 10 15 Gly Thr Glu Leu Thr Gln Val Leu Pro Thr Asn Pro GluGlu Ser Trp 20 25 30 Gln Val Tyr Ser Ser Ala Gln Asp Ser Glu Gly Arg CysIle Cys Thr 35 40 45 Val Val Ala Pro Gln Gln Thr Met Cys Ser Arg Asp AlaArg Thr Lys 50 55 60 Gln Leu Arg Gln Leu Leu Glu Lys Val Gln Asn Met SerGln Ser Ile 65 70 75 80 Glu Val Leu Asp Arg Arg Thr Gln Arg Asp Leu GlnTyr Val Glu Lys 85 90 95 Met Glu Asn Gln Met Arg Gly Leu Glu Ser Lys PheLys Gln Val Glu 100 105 110 Glu Ser His Lys Gln His Leu Ala Arg Gln PheLys Ala Ile Lys Ala 115 120 125 Lys Met Glu Glu Leu Arg Pro Leu Ile ProVal Leu Glu Glu Tyr Lys 130 135 140 Ala Asp Ala Lys Leu Val Leu Gln PheLys Glu Glu Val Gln Asn Leu 145 150 155 160 Thr Ser Val Leu Asn Glu LeuGln Glu Glu Ile Gly Ala Tyr Asp Tyr 165 170 175 Glu Glu Leu Gln Asn ArgVal Ser Asn Leu Glu Glu Arg Leu Arg Ala 180 185 190 Cys Met Gln Lys LeuAla Cys Gly Lys Leu Thr Gly Ile Ser Asp Pro 195 200 205 Ile Thr Ile LysThr Ser Gly Ser Arg Phe Gly Ser Trp Met Thr Asp 210 215 220 Pro Leu AlaPro Glu Gly Glu Asn Lys Val Trp Tyr Met Asp Ser Tyr 225 230 235 240 HisAsn Asn Arg Phe Val Arg Glu Tyr Lys Ser Met Ala Asp Phe Met 245 250 255Asn Thr Asp Asn Phe Thr Ser His Arg Leu Pro His Pro Trp Ser Gly 260 265270 Thr Gly Gln Val Val Tyr Asn Gly Ser Ile Tyr Phe Asn Lys Tyr Gln 275280 285 Ser His Ile Ile Ile Arg Phe Asp Leu Lys Thr Glu Thr Ile Leu Lys290 295 300 Thr Arg Ser Leu Asp Tyr Ala Gly Tyr Asn Asn Met Tyr His TyrAla 305 310 315 320 Trp Gly Gly His Ser Asp Ile Asp Leu Met Val Asp GluAsn Gly Leu 325 330 335 Trp Ala Val Tyr Ala Thr Asn Gln Asn Ala Gly AsnIle Val Ile Ser 340 345 350 Lys Leu Asp Pro Asn Thr Leu Gln Ser Leu GlnThr Trp Asn Thr Ser 355 360 365 Tyr Pro Lys Arg Ser Ala Gly Glu Ala PheIle Ile Cys Gly Thr Leu 370 375 380 Tyr Val Thr Asn Gly Tyr Ser Gly GlyThr Lys Val His Tyr Ala Tyr 385 390 395 400 Gln Thr Asn Ala Ser Thr TyrGlu Tyr Ile Asp Ile Pro Phe Gln Asn 405 410 415 Lys Tyr Ser His Ile SerMet Leu Asp Tyr Asn Pro Lys Asp Arg Ala 420 425 430 Leu Tyr Ala Trp AsnAsn Gly His Gln Ile Leu Tyr Asn Val Thr Leu 435 440 445 Phe His Val IleArg Ser Asp Glu Leu 450 455 64 457 PRT Rattus norvegicus 64 Met Gln ProAla Arg Lys Leu Leu Ser Leu Leu Val Leu Leu Val Met 1 5 10 15 Gly ThrGlu Leu Thr Gln Val Leu Pro Thr Asn Pro Glu Glu Ser Trp 20 25 30 Gln ValTyr Ser Ser Ala Gln Asp Ser Glu Gly Arg Cys Ile Cys Thr 35 40 45 Val ValAla Pro Gln Gln Thr Met Cys Ser Arg Asp Ala Arg Thr Lys 50 55 60 Gln LeuArg Gln Leu Leu Glu Lys Val Gln Asn Met Ser Gln Ser Ile 65 70 75 80 GluVal Leu Asp Arg Arg Thr Gln Arg Asp Leu Gln Tyr Val Glu Lys 85 90 95 MetGlu Asn Gln Met Lys Gly Leu Glu Ser Lys Phe Arg Gln Val Glu 100 105 110Glu Ser His Lys Gln His Leu Ala Arg Gln Phe Lys Ala Ile Lys Ala 115 120125 Lys Met Asp Glu Leu Arg Pro Leu Ile Pro Val Leu Glu Glu Tyr Lys 130135 140 Ala Asp Ala Lys Leu Val Leu Gln Phe Lys Glu Glu Val Gln Asn Leu145 150 155 160 Thr Ser Val Leu Asn Glu Leu Gln Glu Glu Ile Gly Ala TyrAsp Tyr 165 170 175 Asp Glu Leu Gln Ser Arg Val Ser Asn Leu Glu Glu ArgLeu Arg Ala 180 185 190 Cys Met Gln Lys Leu Ala Cys Gly Lys Leu Thr GlyIle Ser Asp Pro 195 200 205 Val Thr Val Lys Thr Ser Gly Ser Arg Phe GlySer Trp Met Thr Asp 210 215 220 Pro Leu Ala Pro Glu Gly Asp Asn Arg ValTrp Tyr Met Asp Gly Tyr 225 230 235 240 His Asn Asn Arg Phe Val Arg GluTyr Lys Ser Met Val Asp Phe Met 245 250 255 Asn Thr Asp Asn Phe Thr SerHis Arg Leu Pro His Pro Trp Ser Gly 260 265 270 Thr Gly Gln Val Val TyrAsn Gly Ser Ile Tyr Phe Asn Lys Phe Gln 275 280 285 Ser His Ile Ile IleArg Phe Asp Leu Lys Thr Glu Thr Ile Leu Lys 290 295 300 Thr Arg Ser LeuAsp Tyr Ala Gly Tyr Asn Asn Met Tyr His Tyr Ala 305 310 315 320 Trp GlyGly His Ser Asp Ile Asp Leu Met Val Asp Glu Asn Gly Leu 325 330 335 TrpAla Val Tyr Ala Thr Asn Gln Asn Ala Gly Asn Ile Val Ile Ser 340 345 350Lys Leu Asp Pro Val Ser Leu Gln Ile Leu Gln Thr Trp Asn Thr Ser 355 360365 Tyr Pro Lys Arg Ser Ala Gly Glu Ala Phe Ile Ile Cys Gly Thr Leu 370375 380 Tyr Val Thr Asn Gly Tyr Ser Gly Gly Thr Lys Val His Tyr Ala Tyr385 390 395 400 Gln Thr Asn Ala Ser Thr Tyr Glu Tyr Ile Asp Ile Pro PheGln Asn 405 410 415 Lys Tyr Ser His Ile Ser Met Leu Asp Tyr Asn Pro LysAsp Arg Ala 420 425 430 Leu Tyr Ala Trp Asn Asn Gly His Gln Thr Leu TyrAsn Val Thr Leu 435 440 445 Phe His Val Ile Arg Ser Asp Glu Leu 450 45565 18 DNA Artificial Sequence Description of Artificial Sequence Ag 267Forward Primer 65 tgcagcgacc atcgttca 18 66 32 DNA Artificial SequenceDescription of Artificial Sequence Ag 267 Probe Primer 66 ctgctgtaacattcatcaat ctggtcactg ca 32 67 17 DNA Artificial Sequence Description ofArtificial Sequence Ag 267 Reverse Primer 67 gggtacatgg gcgccat 17 68 22DNA Artificial Sequence Description of Artificial Sequence Ag1308Forward Primer 68 gagtgtgaca ttccaggaca ct 22 69 23 DNA ArtificialSequence Description of Artificial Sequence Ag1308 Probe Primer 69atggtggcac ctgcctcaac ctg 23 70 19 DNA Artificial Sequence Descriptionof Artificial Sequence Ag1308 Reverse Primer 70 gcactggcac tggtaggaa 1971 22 DNA Artificial Sequence Description of Artificial Sequence Ag2120Forward Primer 71 gctgattgca agaagatgtt tc 22 72 26 DNA ArtificialSequence Description of Artificial Sequence Ag2120 Probe Primer 72ttttgtcagc cctgatttct tcgaca 26 73 22 DNA Artificial SequenceDescription of Artificial Sequence Ag2120 Reverse Primer 73 ccgatatgtcagaatctgca tt 22 74 22 DNA Artificial Sequence Description of ArtificialSequence Ag1493 Forward Primer 74 gtgaaatctg gcgtggagta ta 22 75 23 DNAArtificial Sequence Description of Artificial Sequence Ag1493 ProbePrimer 75 ccttgatggg cacagccatc ttg 23 76 22 DNA Artificial SequenceDescription of Artificial Sequence Ag1493 Reverse Primer 76 gtactggttcccaggtacat ga 22 77 22 DNA Artificial Sequence Description of ArtificialSequence Ag1216 Forward Primer 77 cccgaagaat gaaaagtaca ca 22 78 26 DNAArtificial Sequence Description of Artificial Sequence Ag1216 ProbePrimer 78 cccatggaat tcaagaccct gaacaa 26 79 22 DNA Artificial SequenceDescription of Artificial Sequence Ag1216 Reverse Primer 79 aatgggtagaagttggctct gt 22 80 22 DNA Artificial Sequence Description of ArtificialSequence Ag1215/Ag1382 Forward Primer 80 aacccattat cctgcgtaac at 22 8126 DNA Artificial Sequence Description of Artificial SequenceAg1215/Ag1382 Probe Primer 81 ccccaccact ccatgaagac agagta 26 82 22 DNAArtificial Sequence Description of Artificial Sequence Ag1215/Ag1382Reverse Primer 82 cctacaaagt gaggttcgtt ga 22 83 39 PRT ArtificialSequence Description of Artificial Sequence Domain search result 83 ProGln Asp Pro Trp Ser Arg Cys Glu Asp Ala Gln Cys Trp Asp Lys 1 5 10 15Phe Gly Asp Gly Val Cys Asp Glu Glu Cys Asn Asn Ala Glu Cys Leu 20 25 30Trp Asp Gly Gly Asp Cys Ser 35 84 39 PRT Artificial Sequence Descriptionof Artificial Sequence Domain search result 84 Pro Gln Asp Pro Trp SerArg Cys Glu Asp Ala Gln Cys Trp Asp Lys 1 5 10 15 Phe Gly Asp Gly ValCys Asp Glu Glu Cys Asn Asn Ala Glu Cys Leu 20 25 30 Trp Asp Gly Gly AspCys Ser 35 85 33 PRT Artificial Sequence Description of ArtificialSequence Domain search result 85 Asp Gly Asn Thr Pro Leu His Leu Ala AlaArg Asn Gly His Leu Glu 1 5 10 15 Val Val Lys Leu Leu Leu Glu Ala GlyAla Asp Val Asn Ala Arg Asp 20 25 30 Lys 86 33 PRT Artificial SequenceDescription of Artificial Sequence Domain search result 86 Asp Gly AsnThr Pro Leu His Leu Ala Ala Arg Asn Gly His Leu Glu 1 5 10 15 Val ValLys Leu Leu Leu Glu Ala Gly Ala Asp Val Asn Ala Arg Asp 20 25 30 Lys 8741 PRT Artificial Sequence Description of Artificial Sequence Domainsearch result 87 Asp Ile Asp Glu Cys Ala Ser Gly Asn Pro Cys Gln Asn GlyGly Thr 1 5 10 15 Cys Val Asn Thr Val Gly Ser Tyr Arg Cys Glu Glu CysPro Pro Gly 20 25 30 Tyr Thr Leu Asp Gly Arg Asn Cys Glu 35 40 88 41 PRTArtificial Sequence Description of Artificial Sequence Domain searchresult 88 Asp Ile Asp Glu Cys Ala Ser Gly Asn Pro Cys Gln Asn Gly GlyThr 1 5 10 15 Cys Val Asn Thr Val Gly Ser Tyr Arg Cys Glu Glu Cys ProPro Gly 20 25 30 Tyr Thr Leu Asp Gly Arg Asn Cys Glu 35 40 89 51 PRTArtificial Sequence Description of Artificial Sequence Domain searchresult 89 Asn Pro Phe Ile Cys Asp Cys Glu Leu Arg Trp Leu Leu Arg TrpLeu 1 5 10 15 Glu Ala Asn Arg His Leu Gln Asp Pro Val Asp Leu Arg CysAla Ser 20 25 30 Pro Glu Ser Leu Arg Gly Pro Leu Leu Leu Leu Leu Pro SerSer Phe 35 40 45 Lys Cys Pro 50 90 47 PRT Artificial SequenceDescription of Artificial Sequence Domain search result 90 Arg Cys SerGln Tyr Thr Ser Cys Ser Glu Cys Leu Leu Ala Arg Asp 1 5 10 15 Pro TyrCys Gly Trp Cys Ser Ser Gln Gly Arg Cys Thr Ser Gly Glu 20 25 30 Arg CysAsp Ser Ser Ile Gln Asn Trp Ser Ser Gly Gly Cys Pro 35 40 45 91 430 PRTArtificial Sequence Description of Artificial Sequence Domain searchresult 91 Leu Gln His Leu Leu Leu Asp Glu Asp Asn Gly Thr Leu Tyr ValGly 1 5 10 15 Ala Arg Asn Arg Leu Tyr Ala Leu Ser Leu Asn Leu Ile SerGlu Ala 20 25 30 Glu Val Lys Thr Gly Pro Val Ser Ser Ser Pro Asp Cys GluGlu Cys 35 40 45 Val Ser Lys Gly Lys Asp Pro Pro Thr Asp Cys Gln Asn PheIle Arg 50 55 60 Leu Leu Leu Asp Tyr Asn Ala Asp Arg Leu Leu Val Cys GlyThr Asn 65 70 75 80 Ala Phe Gln Pro Val Cys Arg Leu Ile Asn Leu Gly AsnLeu Asp Arg 85 90 95 Leu Glu Val Gly Arg Glu Ser Gly Arg Gly Arg Cys ProTyr Asp Pro 100 105 110 Gln His Asn Ser Thr Ala Val Leu Val Asp Gly GluLeu Tyr Val Gly 115 120 125 Thr Val Ala Asp Phe Ser Gly Ser Asp Pro AlaIle Tyr Arg Ser Leu 130 135 140 Ser Val Arg Arg Leu Lys Gly Thr Ser GlyPro Ser Leu Arg Thr Val 145 150 155 160 Leu Tyr Asp Ser Arg Trp Leu AsnGlu Pro Asn Phe Val Tyr Ala Phe 165 170 175 Glu Ser Gly Asp Phe Val TyrPhe Phe Phe Arg Glu Thr Ala Val Glu 180 185 190 Asp Glu Asn Cys Gly LysAla Tyr Val Ser Arg Val Ala Arg Val Cys 195 200 205 Lys Asn Asp Val GlyGly Pro Arg Ser Leu Ser Lys Lys Trp Thr Ser 210 215 220 Phe Leu Lys AlaArg Leu Glu Cys Ser Val Pro Gly Glu Ser Pro Phe 225 230 235 240 Tyr PheAsn Glu Leu Gln Ala Ala Phe Leu Leu Pro Ala Gly Ser Glu 245 250 255 SerAsp Asp Val Leu Tyr Gly Val Phe Ser Thr Ser Ser Asn Ser Ile 260 265 270Pro Gly Ser Ala Val Cys Ala Phe Ser Leu Ser Asp Ile Asn Ala Val 275 280285 Phe Asn Glu Pro Phe Lys Glu Cys Glu Thr Gly Asn Ser Gln Trp Leu 290295 300 Pro Tyr Pro Arg Gly Leu Val Pro Phe Pro Arg Pro Gly Thr Cys Pro305 310 315 320 Asn Asn Ser Leu Ser Ser Lys Asp Leu Pro Asp Asp Thr LeuAsn Phe 325 330 335 Ile Lys Thr His Pro Leu Met Asp Glu Ala Val Gln ProLeu Thr Gly 340 345 350 Arg Pro Leu Leu Val Lys Thr Asp Ser Asn Tyr LeuLeu Thr Ser Ile 355 360 365 Ala Val Asp Arg Val Arg Thr Asp Gly Gly AsnTyr Thr Val Leu Phe 370 375 380 Leu Gly Thr Ser Asp Gly Arg Ile Leu LysVal Val Leu Ser Glu Ser 385 390 395 400 Ser Ser Ser Ser Glu Ser Val ValLeu Glu Glu Ile Ser Val Phe Pro 405 410 415 Pro Gly Ser Pro Ile Ser AspLeu Val Ile Ser Pro Lys Lys 420 425 430 92 51 PRT Artificial SequenceDescription of Artificial Sequence Domain search result 92 Trp Gly GluTrp Ser Glu Trp Ser Pro Cys Ser Val Thr Cys Gly Gly 1 5 10 15 Gly ValGln Thr Arg Thr Arg Cys Cys Asn Pro Pro Pro Asn Gly Gly 20 25 30 Gly ProCys Thr Gly Pro Asp Thr Glu Thr Arg Ala Cys Asn Glu Gln 35 40 45 Pro CysPro 50 93 51 PRT Artificial Sequence Description of Artificial SequenceDomain search result 93 Trp Gly Glu Trp Ser Glu Trp Ser Pro Cys Ser ValThr Cys Gly Gly 1 5 10 15 Gly Val Gln Thr Arg Thr Arg Cys Cys Asn ProPro Pro Asn Gly Gly 20 25 30 Gly Pro Cys Thr Gly Pro Asp Thr Glu Thr ArgAla Cys Asn Glu Gln 35 40 45 Pro Cys Pro 50 94 51 PRT ArtificialSequence Description of Artificial Sequence Domain search result 94 TrpGly Glu Trp Ser Glu Trp Ser Pro Cys Ser Val Thr Cys Gly Gly 1 5 10 15Gly Val Gln Thr Arg Thr Arg Cys Cys Asn Pro Pro Pro Asn Gly Gly 20 25 30Gly Pro Cys Thr Gly Pro Asp Thr Glu Thr Arg Ala Cys Asn Glu Gln 35 40 45Pro Cys Pro 50 95 51 PRT Artificial Sequence Description of ArtificialSequence Domain search result 95 Trp Gly Glu Trp Ser Glu Trp Ser Pro CysSer Val Thr Cys Gly Gly 1 5 10 15 Gly Val Gln Thr Arg Thr Arg Cys CysAsn Pro Pro Pro Asn Gly Gly 20 25 30 Gly Pro Cys Thr Gly Pro Asp Thr GluThr Arg Ala Cys Asn Glu Gln 35 40 45 Pro Cys Pro 50 96 48 PRT ArtificialSequence Description of Artificial Sequence Domain search result 96 AsnCys Ser Gln His Thr Ser Cys Ser Ser Cys Leu Ser Ala Pro Asp 1 5 10 15Pro Gly Cys Gly Trp Cys Pro Ser Arg Lys Arg Cys Thr Arg Leu Glu 20 25 30Glu Cys Ser Arg Gly Glu Gly Trp Ser Gln Ser Ser Glu Thr Cys Pro 35 40 4597 431 PRT Artificial Sequence Description of Artificial Sequence Domainsearch result 97 Phe Arg Thr Leu Leu Asp Asp Glu Asp Arg Gly Arg Leu TyrVal Gly 1 5 10 15 Ala Arg Asn His Val Tyr Val Leu Asn Leu Glu Asp LeuSer Glu Val 20 25 30 Leu Asn Leu Lys Ile Gly Trp Pro Ala Ser Cys Glu LysCys Glu Glu 35 40 45 Cys Asn Met Lys Gly Lys Ser Pro Leu Thr Glu Cys ThrAsn Phe Ile 50 55 60 Arg Val Leu Gln Ala Tyr Asn Asp Thr His Leu Tyr ValCys Gly Thr 65 70 75 80 Asn Ala Phe Asn Pro Lys Cys Thr Leu Ile Asn LeuGly Asp Leu Phe 85 90 95 Ser Leu Asp Asn Asp Asn Glu Glu Ser Gly Cys GlyAsp Cys Pro Tyr 100 105 110 Asp Pro Leu Gly Asn Thr Thr Ser Val Leu ValGly Gly Glu Leu Tyr 115 120 125 Ser Gly Thr Ala Ile Asp Phe Ser Gly ArgAsp Pro Ser Ile Arg Arg 130 135 140 Leu Leu Gly Ser His Asp Gly Leu ArgThr Glu Phe His Asp Ser Lys 145 150 155 160 Trp Leu Asn Leu Pro Asn PheVal Asp Ser Tyr Pro Ile His Tyr Val 165 170 175 His Ser Phe Ser Asp AspLys Val Tyr Phe Phe Phe Arg Glu Thr Ala 180 185 190 Val Glu Tyr Ser AsnCys Lys Ala Ile His Ser Arg Val Ala Arg Val 195 200 205 Cys Lys Asn AspPro Gly Gly His Ser Tyr Leu Glu Asn Lys Trp Thr 210 215 220 Thr Phe LeuLys Ala Arg Leu Asn Cys Ser Ile Pro Gly Glu Gly Thr 225 230 235 240 ProPhe Tyr Phe Asn Glu Leu Gln Ala Ala Phe Leu Leu Pro Thr Asp 245 250 255Asn Asp Thr Asp Pro Val Leu Tyr Gly Val Phe Thr Thr Ser Ser Asn 260 265270 Ser Ser Ala Gly Ser Ala Val Cys Ala Phe Ser Met Lys Asp Ile Asn 275280 285 Gln Val Phe Glu Gly Pro Phe Lys His Gln Gly Pro Asn Ser Lys Trp290 295 300 Leu Pro Tyr Arg Gly Arg Val Pro Tyr Pro Arg Pro Gly Gln CysPro 305 310 315 320 Asn Ser Ser Asn Gly Asp Leu Pro Asp Asp Thr Leu AsnPhe Ile Arg 325 330 335 Cys His Pro Leu Met Asp Asp Val Val Pro Pro LeuHis Asn Val Pro 340 345 350 Leu Phe Val Gly Gln Ser Gly Asn Tyr Arg LeuThr Ser Ile Ala Val 355 360 365 Asp Arg Val Glu Ala Gly Asp Gly Gln IleTyr Thr Val Leu Phe Leu 370 375 380 Gly Thr Asp Asp Gly Arg Val Leu LysGln Val Val Leu Ser Arg Ser 385 390 395 400 Ser Ser Ala Ser Tyr Glu ValVal Val Leu Glu Glu Ser Leu Val Phe 405 410 415 Pro Asp Gly Glu Pro IleGln Asn Met Glu Ile Ser Gln Lys Asn 420 425 430 98 86 PRT ArtificialSequence Description of Artificial Sequence Domain search result 98 ProPro Ser Val Thr Val Lys Glu Gly Glu Ser Val Thr Leu Ser Cys 1 5 10 15Glu Ala Ser Gly Asn Pro Pro Pro Thr Val Thr Trp Tyr Lys Gln Gly 20 25 30Gly Lys Leu Leu Ala Glu Ser Gly Arg Phe Ser Val Ser Arg Ser Gly 35 40 45Gly Asn Ser Thr Leu Thr Ile Ser Asn Val Thr Pro Glu Asp Ser Gly 50 55 60Thr Tyr Thr Cys Ala Ala Thr Asn Ser Ser Gly Ser Ala Ser Ser Gly 65 70 7580 Val Thr Leu Thr Val Leu 85 99 181 PRT Artificial Sequence Descriptionof Artificial Sequence Domain search result 99 Met Lys Ser Phe Leu LeuVal Val Asn Ile Leu Ala Leu Thr Leu Pro 1 5 10 15 Phe Leu Ala Ala GluVal Gln Asn Gln Glu Gln Pro Thr Cys Cys Glu 20 25 30 Lys Asp Glu Arg LeuPhe Asn Gln Lys Thr Val Lys Tyr Ile Pro Ile 35 40 45 Tyr Tyr Val Leu AsnArg Tyr Pro Ser Tyr Gly Pro Asn Tyr Tyr Gln 50 55 60 Arg Arg Pro Ala ValPro Ile Asn Asn Pro Phe Met Pro Tyr Pro Tyr 65 70 75 80 Tyr Ala Lys ProAla Val Leu Arg Pro His Ala Gln Ile Pro Gln Trp 85 90 95 Gln Val Leu ProAsn Ile His Pro Pro Thr Val Val Arg His Pro Arg 100 105 110 Pro His ProSer Phe Met Ala Ile Pro Pro Lys Lys Asn Gln Asp Lys 115 120 125 Thr AlaIle Pro Thr Ile Asn Thr Ile Ala Thr Val Glu Pro Thr Pro 130 135 140 ValPro Thr Ala Glu Pro Ile Val Ser Thr Val Val Thr Pro Glu Ala 145 150 155160 Ser Ser Glu Phe Ile Ile Ser Thr Pro Glu Thr Thr Thr Val Ala Val 165170 175 Thr Ser Thr Ala Ala 180 100 395 PRT Artificial SequenceDescription of Artificial Sequence Domain search result 100 Ala Trp IleLeu Ile Ser Ala Ala Leu Val Ile Phe Met Gln Pro Gly 1 5 10 15 Phe AlaLeu Leu Glu Ser Gly Leu Val Arg Ser Lys Asn Val Leu Asn 20 25 30 Ile LeuTyr Lys Asn Phe Gln Asp Val Ala Ile Gly Val Leu Ala Tyr 35 40 45 Trp GlyPhe Gly Tyr Ser Leu Ala Phe Gly Lys Ser Tyr Phe Ser Gly 50 55 60 Phe IleGly Asn Leu Gly Leu Leu Ala Ala Gly Ile Gln Trp Gly Thr 65 70 75 80 LeuPro Asp Gly Leu Phe Phe Leu Phe Gln Leu Met Phe Ala Ala Thr 85 90 95 AlaIle Thr Ile Ile Ser Gly Ala Val Ala Glu Arg Ile Lys Phe Ser 100 105 110Ala Tyr Leu Leu Phe Ser Ala Leu Leu Gly Thr Leu Val Tyr Pro Pro 115 120125 Val Ala His Trp Val Trp Gly Glu Gly Gly Trp Leu Ala Lys Leu Gly 130135 140 Val Leu Val Asp Phe Ala Gly Ser Thr Val Val His Ile Phe Gly Gly145 150 155 160 Tyr Ala Gly Leu Ala Ala Ala Leu Val Leu Gly Pro Arg LeuGly Arg 165 170 175 Phe Thr Lys Asn Glu Ala Ile Thr Pro His Asn Leu ProPhe Ala Met 180 185 190 Leu Gly Thr Leu Leu Leu Trp Phe Gly Trp Phe GlyPhe Asn Ala Gly 195 200 205 Ser Ala Leu Ala Ala Asp Gly Arg Ala Arg AlaAla Ala Val Asn Thr 210 215 220 Asn Leu Ala Ala Ala Gly Gly Ala Leu ThrAla Ile Leu Ile Ser Arg 225 230 235 240 Leu Lys Thr Gly Lys Pro Asn MetLeu Gly Leu Ala Asn Gly Ala Leu 245 250 255 Ala Gly Leu Val Ala Ile ThrPro Ala Cys Gly Val Val Ser Pro Trp 260 265 270 Gly Ala Leu Ile Ile GlyLeu Ile Ala Gly Val Leu Ser Val Leu Gly 275 280 285 Tyr Lys Phe Leu LysGlu Lys Leu Gly Ile Asp Asp Pro Leu Asp Val 290 295 300 Phe Pro Val HisGly Val Gly Gly Ile Trp Gly Gly Ile Ala Val Gly 305 310 315 320 Ile PheAla Ala Leu Tyr Val Thr Ser Gly Ile Ser Gly Gly Leu Leu 325 330 335 TyrGly Asn Ser Lys Gln Leu Gly Val Gln Leu Ile Gly Ile Ala Val 340 345 350Ile Leu Ala Tyr Ala Phe Gly Val Thr Phe Ile Leu Gly Leu Leu Leu 355 360365 Gly Leu Thr Leu Gly Leu Arg Val Ser Glu Glu Glu Glu Lys Val Gly 370375 380 Leu Asp Val Ala Glu His Gly Glu Thr Ala Tyr 385 390 395

What is claimed is:
 1. An isolated polypeptide comprising an amino acidsequence selected from the group consisting of: (a) a mature form of anamino acid sequence selected from the group consisting of SEQ ID NOS:2,4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24; (b) a variant of a matureform of an amino acid sequence selected from the group consisting of SEQID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24, wherein one ormore amino acid residues in said variant differs from the amino acidsequence of said mature form, provided that said variant differs in nomore than 15% of the amino acid residues from the amino acid sequence ofsaid mature form; (c) an amino acid sequence selected from the groupconsisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24;and (d) a variant of an amino acid sequence selected from the groupconsisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24,wherein one or more amino acid residues in said variant differs from theamino acid sequence of said mature form, provided that said variantdiffers in no more than 15% of amino acid residues from said amino acidsequence. 2 The polypeptide of claim 1, wherein said polypeptidecomprises the amino acid sequence of a naturally-occurring allelicvariant of an amino acid sequence selected from the group consisting ofSEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and
 24. 3. Thepolypeptide of claim 2, wherein said allelic variant comprises an aminoacid sequence that is the translation of a nucleic acid sequencediffering by a single nucleotide from a nucleic acid sequence selectedfrom the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17,19, 21, and
 23. 4. The polypeptide of claim 1, wherein the amino acidsequence of said variant comprises a conservative amino acidsubstitution.
 5. An isolated nucleic acid molecule comprising a nucleicacid sequence encoding a polypeptide comprising an amino acid sequenceselected from the group consisting of: (a) a mature form of an aminoacid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6,8, 10, 12, 14, 16, 18, 20, 22, and 24; (b) a variant of a mature form ofan amino acid sequence selected from the group consisting of SEQ IDNOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24, wherein one or moreamino acid residues in said variant differs from the amino acid sequenceof said mature form, provided that said variant differs in no more than15% of the amino acid residues from the amino acid sequence of saidmature form; (c) an amino acid sequence selected from the groupconsisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24;(d) a variant of an amino acid sequence selected from the groupconsisting SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24,wherein one or more amino acid residues in said variant differs from theamino acid sequence of said mature form, provided that said variantdiffers in no more than 15% of amino acid residues from said amino acidsequence; (e) a nucleic acid fragment encoding at least a portion of apolypeptide comprising an amino acid sequence chosen from the groupconsisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24,or a variant of said polypeptide, wherein one or more amino acidresidues in said variant differs from the amino acid sequence of saidmature form, provided that said variant differs in no more than 15% ofamino acid residues from said amino acid sequence; and (f) a nucleicacid molecule comprising the complement of (a), (b), (c), (d) or (e). 6.The nucleic acid molecule of claim 5, wherein the nucleic acid moleculecomprises the nucleotide sequence of a naturally-occurring allelicnucleic acid variant.
 7. The nucleic acid molecule of claim 5, whereinthe nucleic acid molecule encodes a polypeptide comprising the aminoacid sequence of a naturally-occurring polypeptide variant.
 8. Thenucleic acid molecule of claim 5, wherein the nucleic acid moleculediffers by a single nucleotide from a nucleic acid sequence selectedfrom the group consisting of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17,19, 21, and
 23. 9. The nucleic acid molecule of claim 5, wherein saidnucleic acid molecule comprises a nucleotide sequence selected from thegroup consisting of: (a) a nucleotide sequence selected from the groupconsisting of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23;(b) a nucleotide sequence differing by one or more nucleotides from anucleotide sequence selected from the group consisting of SEQ ID NOS: 1,3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23, provided that no more than20% of the nucleotides differ from said nucleotide sequence; (c) anucleic acid fragment of (a); and (d) a nucleic acid fragment of (b).10. The nucleic acid molecule of claim 5, wherein said nucleic acidmolecule hybridizes under stringent conditions to a nucleotide sequencechosen from the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13,15, 17, 19, 21, and 23, or a complement of said nucleotide sequence. 11.The nucleic acid molecule of claim 5, wherein the nucleic acid moleculecomprises a nucleotide sequence selected from the group consisting of:(a) a first nucleotide sequence comprising a coding sequence differingby one or more nucleotide sequences from a coding sequence encoding saidamino acid sequence, provided that no more than 20% of the nucleotidesin the coding sequence in said first nucleotide sequence differ fromsaid coding sequence; (b) an isolated second polynucleotide that is acomplement of the first polynucleotide; and (c) a nucleic acid fragmentof (a) or (b).
 12. A vector comprising the nucleic acid molecule ofclaim
 11. 13. The vector of claim 12, further comprising a promoteroperably-linked to said nucleic acid molecule.
 14. A cell comprising thevector of claim
 12. 15. An antibody that binds immunospecifically to thepolypeptide of claim
 1. 16. The antibody of claim 15, wherein saidantibody is a monoclonal antibody.
 17. The antibody of claim 15, whereinthe antibody is a humanized antibody.
 18. A method for determining thepresence or amount of the polypeptide of claim 1 in a sample, the methodcomprising: (a) providing the sample; (b) contacting the sample with anantibody that binds immunospecifically to the polypeptide; and (c)determining the presence or amount of antibody bound to saidpolypeptide, thereby determining the presence or amount of polypeptidein said sample.
 19. A method for determining the presence or amount ofthe nucleic acid molecule of claim 5 in a sample, the method comprising:(a) providing the sample; (b) contacting the sample with a probe thatbinds to said nucleic acid molecule; and (c) determining the presence oramount of the probe bound to said nucleic acid molecule, therebydetermining the presence or amount of the nucleic acid molecule in saidsample.
 20. The method of claim 19 wherein presence or amount of thenucleic acid molecule is used as a marker for cell or tissue type. 21.The method of claim 20 wherein the cell or tissue type is cancerous. 22.A method of identifying an agent that binds to a polypeptide of claim 1,the method comprising: (a) contacting said polypeptide with said agent;and (b) determining whether said agent binds to said polypeptide. 23.The method of claim 22 wherein the agent is a cellular receptor or adownstream effector.
 24. A method for identifying an agent thatmodulates the expression or activity of the polypeptide of claim 1, themethod comprising: (a) providing a cell expressing said polypeptide; (b)contacting the cell with said agent, and (c) determining whether theagent modulates expression or activity of said polypeptide, whereby analteration in expression or activity of said peptide indicates saidagent modulates expression or activity of said polypeptide.
 25. A methodfor modulating the activity of the polypeptide of claim 1, the methodcomprising contacting a cell sample expressing the polypeptide of saidclaim with a compound that binds to said polypeptide in an amountsufficient to modulate the activity of the polypeptide.
 26. A method oftreating or preventing a MOLX-associated disorder, said methodcomprising administering to a subject in which such treatment orprevention is desired the polypeptide of claim 1 in an amount sufficientto treat or prevent said MOLX-associated disorder in said subject. 27.The method of claim 26 wherein the disorder is selected from the groupconsisting of cardiomyopathy and atherosclerosis.
 28. The method ofclaim 26 wherein the disorder is related to cell signal processing andmetabolic pathway modulation.
 29. The method of claim 26, wherein saidsubject is a human.
 30. A method of treating or preventing aMOLX-associated disorder, said method comprising administering to asubject in which such treatment or prevention is desired the nucleicacid of claim 5 in an amount sufficient to treat or prevent saidMOLX-associated disorder in said subject.
 31. The method of claim 30wherein the disorder is selected from the group consisting ofcardiomyopathy and atherosclerosis.
 32. The method of claim 30 whereinthe disorder is related to cell signal processing and metabolic pathwaymodulation.
 33. The method of claim 30, wherein said subject is a human.34. A method of treating or preventing a MOLX-associated disorder, saidmethod comprising administering to a subject in which such treatment orprevention is desired the antibody of claim 15 in an amount sufficientto treat or prevent said MOLX-associated disorder in said subject. 35.The method of claim 34 wherein the disorder is diabetes.
 36. The methodof claim 34 wherein the disorder is related to cell signal processingand metabolic pathway modulation.
 37. The method of claim 34, whereinthe subject is a human.
 38. A pharmaceutical composition comprising thepolypeptide of claim 1 and a pharmaceutically-acceptable carrier.
 39. Apharmaceutical composition comprising the nucleic acid molecule of claim5 and a pharmaceutically-acceptable carrier.
 40. A pharmaceuticalcomposition comprising the antibody of claim 15 and apharmaceutically-acceptable carrier.
 41. A kit comprising in one or morecontainers, the pharmaceutical composition of claim
 38. 42. A kitcomprising in one or more containers, the pharmaceutical composition ofclaim
 39. 43. A kit comprising in one or more containers, thepharmaceutical composition of claim
 40. 44. A method for determining thepresence of or predisposition to a disease associated with alteredlevels of the polypeptide of claim 1 in a first mammalian subject, themethod comprising: (a) measuring the level of expression of thepolypeptide in a sample from the first mammalian subject; and (b)comparing the amount of said polypeptide in the sample of step (a) tothe amount of the polypeptide present in a control sample from a secondmammalian subject known not to have, or not to be predisposed to, saiddisease; wherein an alteration in the expression level of thepolypeptide in the first subject as compared to the control sampleindicates the presence of or predisposition to said disease.
 45. Themethod of claim 44 wherein the predisposition is to cancers.
 46. Amethod for determining the presence of or predisposition to a diseaseassociated with altered levels of the nucleic acid molecule of claim 5in a first mammalian subject, the method comprising: (a) measuring theamount of the nucleic acid in a sample from the first mammalian subject;and (b) comparing the amount of said nucleic acid in the sample of step(a) to the amount of the nucleic acid present in a control sample from asecond mammalian subject known not to have or not be predisposed to, thedisease; wherein an alteration in the level of the nucleic acid in thefirst subject as compared to the control sample indicates the presenceof or predisposition to the disease.
 47. The method of claim 46 whereinthe predisposition is to a cancer.
 48. A method of treating apathological state in a mammal, the method comprising administering tothe mammal a polypeptide in an amount that is sufficient to alleviatethe pathological state, wherein the polypeptide is a polypeptide havingan amino acid sequence at least 95% identical to a polypeptidecomprising an amino acid sequence of at least one of SEQ ID NOS:2, 4, 6,8, 10, 12, 14, 16, 18, 20, 22, and 24, or a biologically active fragmentthereof.
 49. A method of treating a pathological state in a mammal, themethod comprising administering to the mammal the antibody of claim 15in an amount sufficient to alleviate the pathological state.
 50. Amethod for the screening of a candidate substance interacting with anolfactory receptor polypeptide selected from the group consisting of SEQID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24, or fragments orvariants thereof, comprises the following steps: a) providing apolypeptide selected from the group consisting of the sequences of SEQID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24, or a peptidefragment or a variant thereof; b) obtaining a candidate substance; c)bringing into contact said polypeptide with said candidate substance;and d) detecting the complexes formed between said polypeptide and saidcandidate substance.
 51. A method for the screening of ligand moleculesinteracting with an olfactory receptor polypeptide selected from thegroup consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22,and 24, wherein said method comprises: a) providing a recombinanteukaryotic host cell containing a nucleic acid encoding a polypeptideselected from the group consisting of the polypeptides comprising theamino acid sequences SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22,and 24; b) preparing membrane extracts of said recombinant eukaryotichost cell; c) bringing into contact the membrane extracts prepared atstep b) with a selected ligand molecule; and d) detecting the productionlevel of second messengers metabolites.
 52. A method for the screeningof ligand molecules interacting with an olfactory receptor polypeptideselected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14,16, 18, 20, 22, and 24, wherein said method comprises: a) providing anadenovirus containing a nucleic acid encoding a polypeptide selectedfrom the group consisting of polypeptides comprising the amino acidsequences SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24; b)infecting an olfactory epithelium with said adenovirus; c) bringing intocontact the olfactory epithelium b) with a selected ligand molecule; andd) detecting the increase of the response to said ligand molecule.